Analogs of proxisome proliferator activated receptor (PPAR) agonists and methods of using the same

ABSTRACT

Peroxisome proliferator activated receptor (PPAR) compounds, and methods of using the same for treating bone fractures, treating osteoporosis and/or metabolic bone diseases, and inducing osteogenesis and/or chondrogenesis, are disclosed.

RELATED APPLICATIONS

The present application is divisional application of Ser. No. 16/246,614filed Jan. 14, 2019, now U.S. Pat. No. 10,776,461 issued Sep. 15, 2020,which is a divisional application of Ser. No. 15/699,054 filed Sep. 8,2017, now U.S. Pat. No. 10,181,018 issued Jan. 15, 2019, which is acontinuation-in-part of U.S. Ser. No. 15/593,750 filed May 12, 2017, nowU.S. Pat. No. 10,351,541 issued Jul. 16, 2019, which is a divisionalapplication of U.S. Ser. No. 14/773,022 filed Sep. 4, 2015, now U.S.Pat. No. 9,695,137 issued Jul. 4, 2017, which is a national stageapplication filed under 35 USC § 371 of international applicationPCT/US2014/027817 filed Mar. 14, 2014, which claims priority to U.S.Provisional Application Ser. No. 61/786,030, filed under 35 U.S.C. §111(b) on Mar. 14, 2013, the disclosures of which are expresslyincorporated herein by reference in their entireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

The invention was made with no government support. The government has norights in the invention.

TECHNICAL FIELD

The present disclosure relates to the field of compounds, compositions,and methods useful for the treatment or prevention of osteoporosis,osteoarthritis, metabolic bone disorders, fracture management, and othermusculoskeletal disorders.

BACKGROUND OF THE INVENTION

Osteoporosis is a silent disease of bones that affects tens of millionsof people over the age of 50. The disease results in decreased bonemineral density and ultimately bone fracture. Osteoporosis can lead toacute and chronic fractures, causing significant morbidity and mortalityto patients. Other metabolic bone diseases can similarly result inweakened bones and fractures. Currently, the best medications availablecan reduce recurrent fracture risk only 65% of the time, and areassociated with significant risks such as avascular necrosis of thetemporomandibular joints, subtrochanteric femur fractures, and malignantbone tumors.

Osteoarthritis is the most common joint disorder in the world, andaffects the majority of people over the age of 65. Osteoarthritis is adisease of cartilage and bone that results in the wearing away of thelining of the joint, and ultimately bone-on-bone changes. Osteoarthritiscan lead to crippling joint pain and deformity, causing significantmorbidity to patients. Currently, there are no medical treatmentsavailable to prevent or halt the progression of osteoarthritis. Thestandard of care for treating osteoarthritis dictates supportive painmanagement measures such as medications, physical therapy, braces,lifestyle changes, and activity modifications, until a patient can nolonger tolerate the pain, at which point a joint fusion or replacementmay be performed.

It would be advantageous to develop effective ways of preventing ortreating osteoporosis, osteoarthritis, metabolic bone disorders,fracture management, and other musculoskeletal disorders.

SUMMARY OF THE INVENTION

Provided herein is a method of inducing osteogenesis or chondrogenesis,the method comprising treating mammalian stem cells with an effectiveamount of one or more of a PPARδ agonist and a 20-OH-PGE₂ antagonist,whereby the mammalian stem cells differentiate into a cell of osteoblastor chondroblast lineage.

In a first aspect, there is provided a method of inducing osteogenesisor chondrogenesis which includes: administering an effective amount of apharmaceutical composition to a mammalian patient in need thereof, wherethe pharmaceutical composition comprises a peroxisome proliferatoractivated receptor (PPAR) compound in an amount sufficient to promptstem cells in the patient to contribute toward bone formation, and apharmaceutically acceptable carrier, excipient, diluent or adjuvant;wherein the PPAR compound has a chemical structure of Formula I:

wherein

-   -   X is O, S, NH, or N-alkyl;    -   R₁ is H or alkyl;    -   R₂ is H or alkyl;    -   R₃ is H or CF₃;    -   R₄ is H, CF₃ or halide; and    -   R₅ is H or alkyl;    -   except when X is NCH₃; R₁ is H; R₂ is H; R₃ is CF₃; R₄ is H; and        R₅ is H, and the method comprised inducing osteogenesis;    -   and salts, isomers, solvates, hydrates, polymorphs, and prodrugs        thereof.

In certain embodiments, the administration is by surgical implantationincluding allograft bone, bone substitutes or bone scaffold matrices, orby localized injection of liquid or gel formulations or delivery systemsto or near the bone.

In certain embodiments, the administration is by an intravenous,intramuscular or subcutaneous injection of liquid or gel formulations ordelivery systems.

In another aspect, there is provided a method of inducing osteogenesisor chondrogenesis which includes administering induced stem cells to amammalian patient in need thereof; wherein the induced stem cells arederived from incubating stem cells with a pharmaceutical compositioncomprising a peroxisome proliferator activated receptor (PPAR) compoundhaving a chemical structure of Formula I.

In certain embodiments, the mammalian patient is a human and the stemcells are either harvested from the same patient or supplied fromanother mammalian donor.

In certain embodiments, the stem cells are present in a human patient inneed of therapy for osteoarthritis, cartilage disorder, bone fracture,osteoporosis, metabolic bone disease, avascular necrosis, or concurrentwith skeletal surgery.

In certain embodiments, the stem cells are present in a culture mediaafter either being harvested from a human patient or another mammal; andwherein after treatment are administered to a human patient as a therapyfor osteoarthritis, bone fracture, osteoporosis, metabolic bone disease,avascular necrosis or concurrent with skeletal surgery.

In certain embodiments, the patient has one or more of: injury toarticular cartilage; osteoarthritis; costochondritis; herniation;achondroplasia; relapsing polychondritis; benign or non-cancerouschondroma; and, malignant or cancerous chondrosarcoma.

In another aspect, there is provided a compound having a structure ofFormula I:

wherein:

-   -   X is O, S, NH, NCH₃ NCH₂CH₃, NCH₂CH₂CH₃ or NCH(CH₃)₂;    -   R₁ is H, CH₃, CH₂CH₃ or CH(CH₃)₂;    -   R₂ is H or CH₃;    -   R₃ is H or CF₃;    -   R₄ is H, F or CF₃; and    -   R₅ is H, CH₃ or CH₂CH₃;    -   and salts, isomers, stereoisomers, enantiomers, racemates,        solvates, hydrates, polymorphs, and prodrugs thereof.

In another aspect, there is provided a compound having a structure offormula II:

-   -   wherein:    -   X is O, S, NH, or N-Alkyl;    -   R₁ is H or alkyl;    -   R₂ is H or alkyl;    -   R₃ is H or CF₃;    -   R₄ is H, CF₃ or halide;    -   R₅ is H, alkyl or CF₃; and        Y is

-   -   and salts, isomers, solvates, hydrates, polymorphs, and prodrugs        thereof.

In another aspect, there is provided a method of inducing osteogenesisor chondrogenesis, comprising: administering an effective amount of apharmaceutical composition to a mammalian patient in need thereof eitherdirectly to the patient or by harvesting stem cells from the patient ora suitable donor, treating the isolated stem cells and then deliveringthe treated stem cells to the patient, where the compound has a chemicalstructure of Formula II.

In another aspect, there is provided a compound having a structure offormula III:

-   -   wherein:    -   X is O, S, NH, or N-Alkyl;    -   R₁ is H or alkyl;    -   R₂ is H or alkyl;    -   R₃ is H or CF₃;    -   R₄ is H, CF₃ or halide;    -   R₅ is H, alkyl or CF₃; and        Y is

and salts, isomers, solvates, hydrates, polymorphs, and prodrugsthereof.

In another aspect, there is provided a method of inducing osteogenesisor chondrogenesis, comprising: administering an effective amount of apharmaceutical composition to a mammalian patient in need thereof eitherdirectly to the patient or by harvesting stem cells from the patient ora suitable donor, treating the isolated stem cells and then deliveringthe treated stem cells to the patient, where the compound has a chemicalstructure of Formula III.

In another aspect, there is provided a compound having a structure offormula IV or V:

wherein:

-   -   R₁ is H or alkyl;    -   R₂ is H or alkyl;    -   R₃ is H or CF₃;    -   R₄ is H, CF₃ or halide; and R₅ is H or alkyl;    -   and salts, isomers, solvates, hydrates, polymorphs, and prodrugs        thereof.

In another aspect, there is provided a method of inducing osteogenesisor chondrogenesis, comprising: administering an effective amount of apharmaceutical composition to a mammalian patient in need thereof eitherdirectly to the patient or by harvesting stem cells from the patient ora suitable donor, treating the isolated stem cells and then deliveringthe treated stem cells to the patient, where the compound has a chemicalstructure of Formula IV or V.

In another aspect, there is provided a pharmaceutical compositioncomprising: a compound of Formula I; and one or more of apharmaceutically acceptable carrier, excipient, diluent or adjuvant.

In another aspect, there is provided a method for making the compound ofFormula I, where X=S, comprising following scheme 3 synthesis.

In another aspect, there is provided a method for making the compound ofFormula I, where X=NH, comprising following scheme 4 synthesis.

In another aspect, there is provided a method for making the compound ofFormula I, where X=CH₃, NCH₃ comprising following scheme 5 synthesis.

In another aspect, there is provided a method for making the compound ofFormula I, where X=alkyl, N-Alkyl comprising following scheme 6synthesis.

In other aspects pertaining to chemical syntheses, further methods areprovided in additional schemes 7 to 14 and their associated experimentalexamples.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file may contain one or more drawings executedin color and/or one or more photographs. Copies of this patent or patentapplication publication with color drawing(s) and/or photograph(s) willbe provided by the U.S. Patent and Trademark Office upon request andpayment of the necessary fees.

FIG. 1 : Increased osteogenic formation from MSCs treated with JM-4-57(X=O, R₁=R₂=R₅=H, R₃=CF₃, R₄=F). Note that activity peaks at 10 μM.

FIG. 2 : Increased osteogenic formation from MSCs treated with BK-4-03(X=NH, R₁=R₂=R₄=R₅=H and R₃=CF₃).

FIG. 3 : Increased osteogenic formation from MSCs treated with BK-4-04(X=S, R₁=R₂=R₄=R₅=H and R₃=CF₃).

FIG. 4 : Increased osteogenic formation from MSCs treated with BK-4-15(X=NCH₃, R₁=R₂=R₄=R₅=H and R₃=CF₃).

FIG. 5 : Table I—Structure of GW0742, chemical template for test agents,and summary of results for several compounds tested in the MSC assaywith concomitant assessment of fat cell formation.

FIG. 6 : Scheme 1—Eastern half synthesis.

FIG. 7 : Scheme 2—O-series synthesis.

FIG. 8 : Scheme 3—S-series synthesis.

FIG. 9 : Scheme 4—NH-series synthesis.

FIG. 10 : Scheme 5—N-Methyl synthesis.

FIG. 11 : Scheme 6—N-Alkyl synthesis.

FIG. 12 : Scheme 7—R₁& R₂Western Ring Analogs Group #1.

FIG. 13 : Scheme 8—R₁& R₂ Western Ring Analogs Group #2.

FIG. 14 : Scheme 9—Central Heterocycle “Thiazole-flip”.

FIG. 15 : Scheme 10—Central Heterocycle Triazole Synthesis.

FIG. 16 : Scheme 11—Carboxylic Acid Bioisostere 44.

FIG. 17 : Scheme 12—Carboxylic Acid Bioisosteres 49 and 51.

FIG. 18 : Scheme 13—Carboxylic Acid Bioisosteres 53, 56, and 57Syntheses.

FIG. 19 : Scheme 14—Naphthalene Sulfonic Acid 61 and Amide 61 Syntheses.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments are described herein in the context of PPARanalogues, and methods of using the same. Those of ordinary skill in theart will realize that the following detailed description of theembodiments is illustrative only and not intended to be in any waylimiting. Other embodiments will readily suggest themselves to suchskilled persons having the benefit of this disclosure. Reference to an“embodiment,” “aspect,” or “example” herein indicate that theembodiments of the invention so described may include a particularfeature, structure, or characteristic, but not every embodimentnecessarily includes the particular feature, structure, orcharacteristic. Further, repeated use of the phrase “in one embodiment”does not necessarily refer to the same embodiment, although it may doso.

In the interest of clarity, not all of the routine features of theimplementations or processes described herein are shown and described.It will, of course, be appreciated that in the development of any suchactual implementation, numerous implementation-specific decisions willbe made in order to achieve the developer's specific goals, such ascompliance with application- and business-related constraints, and thatthese specific goals will vary from one implementation to another andfrom one developer to another. Moreover, it will be appreciated thatsuch a development effort might be complex and time-consuming, but wouldnevertheless be a routine undertaking for those of ordinary skill in theart having the benefit of this disclosure.

Definitions

The term “PPAR” refers to Peroxisome Proliferator Activated Receptors,which are orphan receptors belonging to the steroid/retinoid receptorsuperfamily of ligand-activated transcription factors. Three mammalianPPARs have been identified, termed PPARα, PPARγ, and PPARδ. PPARsregulate expression of target genes by binding to DNA response elementsas heterodimers with the retinoid X receptor.

The term “pharmacophoric mimic” refers to a compound or functional grouphaving the steric and electronic features necessary for molecularrecognition by a biological macromolecule similar to that of anothercompound or functional group.

The term “alkyl” as used herein refers to monovalent alkyl groups, whichare saturated hydrocarbons, preferably having from 1 to 10 carbon atomsand more preferably 1 to 6 carbon atoms. This term is exemplified bygroups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,n-hexyl, and the like.

Unless stereochemistry is specifically indicated, all stereoisomers ofthe compounds herein are included, as pure compounds as well as mixturesthereof.

Some of the crystalline forms for the compounds may exist as polymorphsand as such are included. In addition, some of the compounds herein mayform solvates with water (i.e., hydrates) or common organic solvents,which are also included.

Protected forms of the compounds herein are further included. A varietyof protecting groups are possible.

Prodrugs of the compounds herein are included. In general, such prodrugsare functional derivatives of the compounds that are readily convertiblein vivo into the required compound. Thus, in the methods of treatment,the term “administering” includes the treatment of the various disordersdescribed with the compound specifically disclosed or with a compoundwhich may not be specifically disclosed, but which converts to thespecified compound in vivo after administration to a subject in needthereof. A simple example of a prodrug, not meant to be limiting in anymanner, would be an alkyl ester of the acidic groups contained at R₅within Formula I, or of the acidic sulfate, phosphate or borate groupspossible for Y in Formula II.

The term “solvate” refers to a pharmaceutically acceptable solid form ofa specified compound containing solvent molecules as part of the crystalstructure. A solvate typically retains at least some of the biologicaleffectiveness of such compound. Solvates can have differentsolubilities, hygroscopicities, stabilities, and other properties.Examples of solvates include, but are not limited to, compounds incombination with water, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, or ethanolamine. Solvates are sometimes termed“pseudopolymorphs.” The term “hydrate” refers to a solvate with water.

The term “racemate” refers to a mixture that contains an equal amount ofenantiomers.

It will be appreciated by one of ordinary skill in the art thatasymmetric centers may exist in any of the compounds disclosed herein.Thus, the compounds may be in the form of an individual enantiomer,diastereomer, or geometric isomer, or may be in the form of a mixture ofstereoisomers. In certain embodiments, the compounds are enantiopurecompounds. In certain other embodiments, mixtures of stereoisomers ordiastereomers are provided. Additionally, the compounds encompass both(Z) and (E) double bond isomers (or cis and trans isomers) unlessotherwise specifically designated. Thus, compounds generally depicted instructures herein encompass those structures in which double bonds are(Z) or (E).

It will also be appreciated that any of the compounds described hereinmay be substituted with any number of substituents or functionalmoieties. In general, the term “substituted” whether preceded by theterm “optionally” or not, and substituents contained in formulas, referto the replacement of hydrogen atoms in a given structure with aspecified substituent. When more than one position in any givenstructure may be substituted with more than one substituent selectedfrom a specified group, the substituent may be either the same ordifferent at every position.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents. For purposes of explanation herein, heteroatoms such asnitrogen may have hydrogen substituents and/or any permissiblesubstituents of organic compounds described herein which satisfy thevalencies of the heteroatoms. Furthermore, there is not any intention tobe limited in any manner by the permissible substituents.

General Description

Mesenchymal stem cells are stem cells that can develop into connectivetissue throughout the body, such as bone, fat, and cartilage. Thepresent disclosure is aimed at directing mesenchymal stem cells towardosteogenesis or chondrogenesis as opposed to adipogenesis, therebyinducing bone formation over fat formation. The compounds, compositions,and methods described herein are thus useful in the treatment and/orprevention of musculoskeletal disorders such as osteoporosis,osteoarthritis, metabolic and bone disease, as well as for fracturemanagement and prosthetic integration.

Further provided herein is a method of inducing osteogenesis, the methodcomprising: contacting a mammalian cell with an effective amount of atleast one pharmaceutical composition described herein, whereby themammalian cell differentiates into a cell of an osteoblast lineage, orwhereby the mammalian cell differentiates into a cell of a chondroblastlineage.

In certain embodiments, the mammalian cell is an in vivo mammalian cell.

In certain embodiments, the mammalian cell is a mesenchymal stem cell.

In certain embodiments, the stem cell is isolated from a primate.

In certain embodiments, the primate is a human.

In certain embodiments, the step of contacting is by oral administrationof the compound to the mammal.

In certain embodiments, the step of contacting is by intravenousadministration of the compound to the mammal.

In certain embodiments the step of contacting is by subcutaneousadministration of the compound to the mammal.

In certain embodiments, the method further comprises detectingdifferentiation of the mammalian cell into an osteocyte cell of anosteoblast lineage.

In certain embodiments, the method further comprises detectingdifferentiation of the mammalian cell into a chondrocyte cell of achondroblast lineage.

In certain embodiments, wherein the mammalian cell is attached to asolid support.

In certain embodiments, the solid support is a three dimensional matrix.

In certain embodiments, the solid support is a planar surface.

Further provided herein is a method of treating a bone disorder,comprising: contacting a mammalian cell with a pharmaceuticalcomposition as described herein, whereby the mammalian celldifferentiates into a cell of an osteoblast lineage, wherein the bonedisorder is associated with defective osteoblasts.

In certain embodiments, the bone disorder is osteoporosis.

In certain embodiments, the method further comprises administering thecell of an osteoblast lineage to an individual with the disorder,thereby treating the disorder.

In certain embodiments, the administration is by surgical implantation.

Further provided herein is a method of treating a cartilage disorder,comprising: contacting a mammalian cell with a pharmaceuticalcomposition as described herein, whereby the mammalian celldifferentiates into a cell of a chondroblast lineage, wherein the bonedisorder is associated with defective chondroblasts.

In certain embodiments, the cartilage disorder is one or more of: injuryto articular cartilage; osteoarthritis; costochondritis; herniation;achondroplasia; relapsing polychondritis; benign or non-cancerouschondroma; and, malignant or cancerous chondrosarcoma.

Further provided herein is a method for inducing chondrogenesis leadingto cartilage formation or chondrogenesis leading to cartilage formationthat further mediates formation of new bone tissue in a vertebrate, themethod comprising administering a therapeutically effective amount of apharmaceutical composition as described herein to the vertebrate.

In certain embodiments, the administration is local or systemic.

Further provided herein is a method for promoting chondrogenesis at asite of skeletal surgery in a vertebrate, the method comprisingdelivering a pharmaceutical composition as described herein at the siteof skeletal surgery wherein such delivery induces chondrogenesis leadingto cartilage formation at the site or chondrogenesis leading tocartilage formation that further mediates formation of new bone tissueat the site.

In accordance with the present disclosure, there are provided hereincompounds that are analogs of PPARδ and 20-OH-PGE₂. The analog compoundsserve as either agonists to compounds that promote bone formation orantagonists to compounds that induce adipogenesis.

Example

Osteogenesis

Human bone marrow-derived mesenchymal stem cells (MSCs) were takenthrough 2-3 passages and distributed across a 24 well plate at a densityof 1×10⁵ cells/cm². The plates were cultured in α-MEM with 20% FBS for 1day at 37° C. On day 2 the medium was switched to osteogenic media (StemX-Vivo, R&D System, Minneapolis, Minn.) containing 10% FBS plus 50 μg/mlascorbic acid and 3 mM β-glycerol-phosphate. MSCs were cultured in theosteogenic medium without (vehicle negative control) or with test agentsat 1, 2, 4, 10 or 20 μM supplied every 2nd day for 21 days. GW 0427(standard PPAR ligand as positive control) was delivered by the sameregimen on every plate to account for experimental variation.

Quantification of Osteoblast Mineralization

Plates were washed twice with ice-cold PBS and incubated in 50 mMTris-HCl (pH 7.6). The cells were treated with 2% Alizarin Red S (pH4.2) for 10 min and then washed with distilled water. Stained cells werevisualized by phase-contrast microscopy to determine cell morphology andto verify the presence of mineralized nodules (red images). Theintensities of the images were assessed by Image-Pro Analyzer (MediaCybernetics, Inc., Bethesda, Md.).

Results

Representative results for test agents having O, NH, S and N(CH₃)X-linkages are respectively displayed in FIGS. 1-4 .

FIG. 5 —Table I provides a structural key for these compounds and asummary of biological data for several additional members within each ofthe four linkage types. FIG. 5 —Table I shows the structure of GW0742,chemical template for test agents, and summary of results for severalcompounds tested in the MSC assay with concomitant assessment of fatcell formation.

Explanatory comments: ‘AD’ indicates formation of fat cells analogous tothose in adipose tissue; ‘OS’ indicates formation of mineral depositsindicative of osteogenesis (‘OS’); For both observations, generalizedscaling was ‘0’ for none observed, ‘+’ for modest, ‘++’ for moderate,‘+++’ for significant, and ‘++++’ for extensive; The term ‘Toxic’indicates that cell viability was affected by the test agent such thatassignment of a scale for either AD or OS became compromised; and, Blankentries indicate that the corresponding dose either was not tested orassessed, the latter generally being due to the observation of toxicityfrom the preceding dose.

Additional notes: A mix of fat and osteogenic effects is regarded asacceptable as long as bone predominates during dose progression, e.g.BK-4-15 exhibits the most preferred profile while the profile forBK-4-30 is not as suitable. While GW0742 initially demonstrates such apreference, its OS activity typically decreased as its dose range wascontinued to 10 and 20 uM such that all of its estimated, averagedeffects at these higher doses have been placed in parentheses.

The chemical synthesis and reaction schemes are shown in FIGS. 6-19 .Note that the numbering of R groups does not correspond to the templatedepicted in FIG. 5 Table I. The final compound designations, however,are identical.

It is intended that any of the compounds disclosed herein could be usedin a medication, a food additive, an injection, or a surgical implantdesigned to treat, ameliorate, or modify, osteoporosis, osteoarthritis,metabolic bone disease, and/or fracture management problems. Thecompounds of the present disclosure could be used to enhance the naturalpathways to direct a patient's own mesenchymal stem cells toward boneand cartilage formation over adipose formation, thereby preventingand/or treating these underlying conditions. The compounds could also beincorporated into a pharmaceutical composition, or could be used totreat isolated stem cells that are then administered to a patient inneed thereof.

Pharmaceutical Compositions

Pharmaceutical compositions of the present disclosure comprise aneffective amount of a compound disclosed herein, and/or additionalagents, dissolved or dispersed in a pharmaceutically acceptable carrier.The phrases “pharmaceutical” or “pharmacologically acceptable” refers tomolecular entities and compositions that produce no adverse, allergic orother untoward reaction when administered to an animal, such as, forexample, a human. The preparation of a pharmaceutical composition thatcontains at least one compound or additional active ingredient will beknown to those of skill in the art in light of the present disclosure,as exemplified by Remington's Pharmaceutical Sciences, 2003,incorporated herein by reference. Moreover, for animal (e.g., human)administration, it is understood that preparations should meetsterility, pyrogenicity, general safety and purity standards as requiredby FDA Office of Biological Standards.

A composition disclosed herein may comprise different types of carriersdepending on whether it is to be administered in solid, liquid oraerosol form, and whether it need to be sterile for such routes ofadministration as injection. Compositions disclosed herein can beadministered intravenously, intradermally, transdermally, intrathecally,intraarterially, intraperitoneally, intranasally, intravaginally,intrarectally, intraosseously, periprosthetically, topically,intramuscularly, subcutaneously, mucosally, intraosseosly,periprosthetically, in utero, orally, topically, locally, via inhalation(e.g., aerosol inhalation), by injection, by infusion, by continuousinfusion, by localized perfusion bathing target cells directly, via acatheter, via a lavage, in cremes, in lipid compositions (e.g.,liposomes), or by other method or any combination of the forgoing aswould be known to one of ordinary skill in the art (see, for example,Remington's Pharmaceutical Sciences, 2003, incorporated herein byreference).

The actual dosage amount of a composition disclosed herein administeredto an animal or human patient can be determined by physical andphysiological factors such as body weight, severity of condition, thetype of disease being treated, previous or concurrent therapeuticinterventions, idiopathy of the patient and on the route ofadministration. Depending upon the dosage and the route ofadministration, the number of administrations of a preferred dosageand/or an effective amount may vary according to the response of thesubject. The practitioner responsible for administration will, in anyevent, determine the concentration of active ingredient(s) in acomposition and appropriate dose(s) for the individual subject.

In certain embodiments, pharmaceutical compositions may comprise, forexample, at least about 0.1% of an active compound. In otherembodiments, an active compound may comprise between about 2% to about75% of the weight of the unit, or between about 25% to about 60%, forexample, and any range derivable therein. Naturally, the amount ofactive compound(s) in each therapeutically useful composition may beprepared is such a way that a suitable dosage will be obtained in anygiven unit dose of the compound. Factors such as solubility,bioavailability, biological half-life, route of administration, productshelf life, as well as other pharmacological considerations will becontemplated by one skilled in the art of preparing such pharmaceuticalformulations, and as such, a variety of dosages and treatment regimensmay be desirable.

In other non-limiting examples, a dose may also comprise from about 1microgram/kg/body weight, about 5 microgram/kg/body weight, about 10microgram/kg/body weight, about 50 microgram/kg/body weight, about 100microgram/kg/body weight, about 200 microgram/kg/body weight, about 350microgram/kg/body weight, about 500 microgram/kg/body weight, about 1milligram/kg/body weight, about 5 milligram/kg/body weight, about 10milligram/kg/body weight, about 50 milligram/kg/body weight, about 100milligram/kg/body weight, about 200 milligram/kg/body weight, about 350milligram/kg/body weight, about 500 milligram/kg/body weight, to about1000 mg/kg/body weight or more per administration, and any rangederivable therein. In non-limiting examples of a derivable range fromthe numbers listed herein, a range of about 5 mg/kg/body weight to about100 mg/kg/body weight, about 5 microgram/kg/body weight to about 500milligram/kg/body weight, etc., can be administered, based on thenumbers described above.

In certain embodiments, a composition herein and/or additional agent isformulated to be administered via an alimentary route. Alimentary routesinclude all possible routes of administration in which the compositionis in direct contact with the alimentary tract. Specifically, thepharmaceutical compositions disclosed herein may be administered orally,buccally, rectally, or sublingually. As such, these compositions may beformulated with an inert diluent or with an assimilable edible carrier,or they may be enclosed in hard- or soft-shell gelatin capsules, theymay be compressed into tablets, or they may be incorporated directlywith the food of the diet.

In further embodiments, a composition described herein may beadministered via a parenteral route. As used herein, the term“parenteral” includes routes that bypass the alimentary tract.Specifically, the pharmaceutical compositions disclosed herein may beadministered, for example but not limited to, intravenously,intradermally, intramuscularly, intraarterially, intrathecally,subcutaneous, or intraperitoneally (U.S. Pat. Nos. 6,753,514, 6,613,308,5,466,468, 5,543,158; 5,641,515; and 5,399,363 are each specificallyincorporated herein by reference in their entirety).

Solutions of the compositions disclosed herein as free bases orpharmacologically acceptable salts may be prepared in water suitablymixed with a surfactant, such as hydroxypropylcellulose. Dispersions mayalso be prepared in glycerol, liquid polyethylene glycols and mixturesthereof, and in oils. Under ordinary conditions of storage and use,these preparations may contain a preservative to prevent the growth ofmicroorganisms. The pharmaceutical forms suitable for injectable useinclude sterile aqueous solutions or dispersions and sterile powders forthe extemporaneous preparation of sterile injectable solutions ordispersions (U.S. Pat. No. 5,466,468, specifically incorporated hereinby reference in its entirety). In most cases, the form must be sterileand must be fluid to the extent that easy injectability exists. Itshould be stable under the conditions of manufacture and storage andshould be preserved against the contaminating action of microorganisms,such as bacteria and fungi. The carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (i.e., glycerol,propylene glycol, liquid polyethylene glycol, and the like), suitablemixtures thereof, and/or vegetable oils. Proper fluidity may bemaintained, for example, by the use of a coating, such as lecithin, bythe maintenance of the required particle size in the case of dispersion,and/or by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, such as, but not limited to, parabens, chlorobutanol,phenol, sorbic acid, thimerosal, and the like. In many cases, it ispreferable to include isotonic agents, for example, sugars or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption such as, for example, aluminum monostearate or gelatin.

For parenteral administration in an aqueous solution, for example, thesolution should be suitably buffered if necessary and the liquid diluentfirst rendered isotonic with sufficient saline or glucose. Theseparticular aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous, and intraperitoneal administration. In thisconnection, sterile aqueous media that can be employed is known to thoseof skill in the art in light of the present disclosure. For example, onedosage may be dissolved in 1 mL of isotonic NaCl solution and eitheradded to 1000 mL of hypodermoclysis fluid or injected at the proposedsite of infusion, (see for example, “Remington's PharmaceuticalSciences” 15th Edition, pages 1035-1038 and 1570-1580). Some variationin dosage will necessarily occur depending on the condition of thesubject being treated. The person responsible for administration will,in any event, determine the appropriate dose for the individual subject.Moreover, for human administration, preparations should meet sterility,pyrogenicity, general safety and purity standards as required by FDAOffice of Biologics standards.

Sterile injectable solutions are prepared by incorporating thecompositions in the required amount in the appropriate solvent withvarious other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized compositions into a sterile vehiclewhich contains the basic dispersion medium and the required otheringredients from those enumerated above. In the case of sterile powdersfor the preparation of sterile injectable solutions, some methods ofpreparation are vacuum-drying and freeze-drying techniques which yield apowder of the active ingredient plus any additional desired ingredientfrom a previously sterile-filtered solution thereof. A powderedcomposition is combined with a liquid carrier such as, e.g., water or asaline solution, with or without a stabilizing agent.

In other embodiments, the compositions may be formulated foradministration via various miscellaneous routes, for example, topical(i.e., transdermal) administration, mucosal administration (intranasal,vaginal, etc.) and/or via inhalation.

Pharmaceutical compositions for topical administration may include thecompositions formulated for a medicated application such as an ointment,paste, cream, or powder. Ointments include all oleaginous, adsorption,emulsion, and water-soluble based compositions for topical application,while creams and lotions are those compositions that include an emulsionbase only. Topically administered medications may contain a penetrationenhancer to facilitate adsorption of the active ingredients through theskin. Suitable penetration enhancers include glycerin, alcohols, alkylmethyl sulfoxides, pyrrolidones and luarocapram. Possible bases forcompositions for topical application include polyethylene glycol,lanolin, cold cream and petrolatum as well as any other suitableabsorption, emulsion or water-soluble ointment base. Topicalpreparations may also include emulsifiers, gelling agents, andantimicrobial preservatives as necessary to preserve the composition andprovide for a homogenous mixture. Transdermal administration of thecompositions may also comprise the use of a “patch.” For example, thepatch may supply one or more compositions at a predetermined rate and ina continuous manner over a fixed period of time.

In certain embodiments, the compositions may be delivered by eye drops,intranasal sprays, inhalation, and/or other aerosol delivery vehicles.Methods for delivering compositions directly to the lungs via nasalaerosol sprays has been described in U.S. Pat. Nos. 5,756,353 and5,804,212 (each specifically incorporated herein by reference in theirentirety). Likewise, the delivery of drugs using intranasalmicroparticle resins (Takenaga et al., 1998) andlysophosphatidyl-glycerol compounds (U.S. Pat. No. 5,725,871,specifically incorporated herein by reference in its entirety) are alsowell-known in the pharmaceutical arts and could be employed to deliverthe compositions described herein. Likewise, transmucosal drug deliveryin the form of a polytetrafluoroethylene support matrix is described inU.S. Pat. No. 5,780,045 (specifically incorporated herein by referencein its entirety), and could be employed to deliver the compositionsdescribed herein.

It is further envisioned the compositions disclosed herein may bedelivered via an aerosol. The term aerosol refers to a colloidal systemof finely divided solid or liquid particles dispersed in a liquefied orpressurized gas propellant. The typical aerosol for inhalation consistsof a suspension of active ingredients in liquid propellant or a mixtureof liquid propellant and a suitable solvent. Suitable propellantsinclude hydrocarbons and hydrocarbon ethers. Suitable containers willvary according to the pressure requirements of the propellant.Administration of the aerosol will vary according to subject's age,weight and the severity and response of the symptoms.

Kits

It is further intended the compounds disclosed herein could be packagedin the form of a kit containing a single or separate containers. Manyembodiments of such kits are possible. For instance, a kit could housetwo containers, the first container comprising a compound of Formula I,and the second container comprising a compound of Formula II. By way offurther non-limiting example, a kit could have a first container housinga solution comprising one or more compounds of Formula I and Formula II,and a second container comprising a syringe configured to inject thesolution. As another example, a kit for the preparation of apharmaceutical composition could have a first container housing one ormore compounds of Formula I and Formula II, and a second containerhousing a pharmaceutically acceptable carrier, excipient, diluent, oradjuvant. Many other variations and embodiments of such kits areenvisioned. The kits typically further include instructions for usingthe components of the kit to practice the subject methods. Theinstructions for practicing the subject methods are generally recordedon a suitable recording medium. For example, the instructions may bepresent in the kits as a package insert or in the labeling of thecontainer of the kit or components thereof. In other embodiments, theinstructions are present as an electronic storage data file present on asuitable computer readable storage medium, such as a flash drive,CD-ROM, or diskette. In other embodiments, the actual instructions arenot present in the kit, but means for obtaining the instructions from aremote source, such as via the internet, are provided. An example ofthis embodiment is a kit that includes a web address where theinstructions can be viewed and/or from which the instructions can bedownloaded. As with the instructions, this means for obtaining theinstructions is recorded on a suitable substrate.

Chemical Syntheses 4-Methyl-2-phenylthiazole-5-carboxylic acid ethylester (2a)

To a suspension of thiobenzamide 1a (6.05 g, 0.044 mol) in 95% ethanolwas added ethyl 2-chloroacetoacetate (6.10 mL, 0.044 mol) and themixture was stirred at reflux temperature for 26 hours. The reactionmixture was concentrated under reduced pressure and the resultingresidue was suspended in ice-cold hexane and stirred for 20 minutes. Thesuspension was filtered and 2a collected as a cream-colored solid (7.434g, 0.030 mol, 68.3%). TLC R_(f) (25% EtOAc/Hexane)=0.63. Mp 84-87° C. ¹HNMR (CDCl₃, 600 MHz): δ ppm 8.19 (2H, d, J=7.32 Hz), 7.56 (1H, t, J=7.32Hz), 7.53 (2H, t, J=7.08 Hz), 4.41 (2H, q, J=7.14 Hz), 2.94 (3H, s),1.41 (3H, t, J=7.14 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ (ppm) 171.25,161.07, 157.83, 133.21, 129.82, 128.10, 122.55, 62.37, 16.29, 14.52 ppm.

4-Methyl-2-phenyl-5-thiazolemethanol (3a)

To a stirred solution of ethyl ester 2a (0.304 g, 1.237 mmol) inanhydrous THF (1 mL) at 0° C. was added 2M lithium aluminum hydridesolution in THF (1.24 ml, 2.48 mmol). The resulting mixture was stirredunder argon at 0° C. for 1.5 hours. The reaction mixture was quenched bythe careful addition of 0.5 ml of water, followed by 2.5 ml of ethylacetate and 0.92 g of anhydrous sodium sulfate. The mixture was stirredfor 15 minutes and was filtered and concentrated under reduced pressureto give 3a as a light-yellow solid (0.215 g, 1.053 mmol, 85.1%). TLCR_(f) (25% EtOAc/Hexane)=0.11. Mp 101-102° C. ¹H NMR (CDCl₃, 600 MHz): δppm 7.88 (2H, d, J=7.92 Hz), 7.41 (3H, m), 4.79 (2H, s), 2.94 (1H, s),2.41 (3H, s).

5-Chloromethyl-4-methyl-2-phenyl-thiazole (4a)

To a stirred solution of alcohol 3a (4.095 g, 0.019 mol) in anhydrousdichloromethane (100 ml) was added triethylamine (5.50 ml, 0.039 mol).The resulting mixture was cooled to 4° C. and methanesulfonyl chloride(2.30 ml, 0.029 mol) was slowly added. The mixture was stirred at 4° C.for 24 hours and then diluted with 100 ml dichloromethane, washed withsaturated NaHCO₃ solution, water, brine, dried with Na₂SO₄, andconcentrated. The residue was purified by column chromatography onsilica gel with 10% ethyl acetate/hexane to give 4a as a light yellowsolid (2.850 g, 0.013 mol, 64.0%). TLC R_(f) (25% EtOAc/Hexane)=0.57. Mp89-90° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.90 (2H, m), 7.43 (3H, m),4.80 (2H, s), 2.50 (3H, s).

Methyl 4-[[4-methyl-2-phenylthiazol-5-yl]methyl]methoxycinnamate (5a)

To a stirred solution of Methyl 4-Hydroxycinnamate (0.142 g, 0.797 mmol)and chloromethyl 4a (0.150 g, 0.670 mmol) in anhydrous acetonitrile (5ml) was added cesium carbonate with partial solubility. The resultingmixture was stirred for 24 hours at room temperature at which TLC showedthat the chloromethyl 4a had been consumed. The reaction mixture wasconcentrated and the residue was dissolved in ethyl acetate and washedwith water, brine, dried with Na₂SO₄, and concentrated. Columnchromatography on silica gel failed to give a pure product and the crudewhite solid 5a collected was moved to the next step without furtherpurification.

4-[[4-Methyl-2-phenylthiazol-5-yl]methyl]methoxycinnamic Acid (BK-3-51)

To a stirred solution of methyl ester 5a was added dropwise 3N NaOH.After 20 hours, the mixture was acidified with 1N HCl to a pH=1-2 andconcentrated. The residue was suspended in ethyl acetate and washed withwater and brine. The aqueous phase was extracted with a separate portionof ethyl acetate and the organic phases were combined, dried with Na₂SO₄and concentrated. The residue was purified by column chromatography onsilica gel to give BK-3-51 as a white solid (0.061 g, 0.173 mmol,41.7%). TLC R_(f) (50% EtOAc/Hexane)=0.17. Mp 209-211° C. ¹H NMR(Acetone-d6, 600 MHz): δ ppm 7.91 (2H, m), 7.67 (2H, d, J=8.76 Hz), 7.55(1H, d, J=15.96 Hz), 7.49 (3H, m), 7.09 (2H, d, J=8.82 Hz), 6.41 (1H, d,J=15.96 Hz), 5.38 (2H, s), 2.46 (4H, s).

Ethyl 4-Methyl-2-[4-(trifluoromethyl)phenyl]-thiazole-5-carboxylate (2b)

In analogy to the procedure described in example 2a,4-(trifluoromethyl)thiobenzamide 1a (1.065 g, 5.190 mmol) was treatedwith ethyl-2-chloroacetoacetate in 95% ethanol to give 2b as acream-colored solid (1.148 g, 3.644 mmol, 70.2%). TLC R_(f) (25%EtOAc/Hexane)=0.69. Mp 89-89.5° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 8.10(2H, d, J=8.04 Hz), 7.73 (2H, d, J=8.16 Hz), 4.39 (2H, q, J=7.14 Hz),2.81 (3H, s), 1.42 (3H, t, J=7.08 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ (ppm)167.87, 162.17, 161.38, 136.16, 132.59 (q, ²J_(FC)=33 Hz), 127.18,126.22 (m), 123.90 (q, ¹J_(FC)=270 Hz), 123.13, 61.61, 17.67, 14.47.Anal. Calcd for C₁₄H₁₂F₃NO₂S (with 0.2 H₂O mol per target): C, 52.73; H,3.92; N, 4.39. Found: C, 52.59; H, 3.85; N, 4.71.

4-Methyl-2-[4-(trifluoromethyl)phenyl]-thiazole-5-methanol (3b)

In analogy to the procedure described in example 3a, ethyl ester 2b(1.320 g, 4.190 mmol) was treated with 2M LiAlH₄ solution in THF to give3b as a yellow solid (0.904 g, 3.308 mmol, 79.0%). TLC R_(f) (25%EtOAc/Hexane)=0.16. Mp 121.5-122° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 8.02(2H, d, J=8.04 Hz), 7.69 (2H, d, J=8.16 Hz), 4.86 (2H, s), 2.48 (3H, s).¹³C NMR (CDCl₃, 150 MHz): δ (ppm) 164.33, 150.91, 136.74, 132.57, 131.63(q, ²J_(FC)=33 Hz), 126.66, 126.08 (m), 124.03 (q, ¹J_(FC)=270 Hz),57.04, 15.27.

5-Chloromethyl-4-methyl-2-[4-(trifluoromethyl)phenyl]-thiazole (4b)

In analogy to the procedure described in example 4a, alcohol 3b (0.883g, 3.231 mmol) was treated with methanesulfonyl chloride andtriethylamine in dry DCM to give 4b as a light yellow solid (0.790 g,2.708 mmol, 83.8%). TLC R_(f) (25% EtOAc/Hexane)=0.53. Mp 68.5-69° C. ¹HNMR (CDCl₃, 600 MHz): δ ppm 8.03 (2H, d, J=8.10 Hz), 7.70 (2H, d, J=8.16Hz), 4.81 (2H, s), 2.52 (3H, s). ¹³C NMR (CDCl₃, 150 MHz): δ (ppm)165.02, 153.25, 136.51, 131.92 (q, ²J_(FC)=33 Hz), 129.06, 126.77,126.12 (m), 123.99 (q, ¹J_(FC)=270 Hz), 37.32, 15.20. Anal. Calcd forC₁₂H₉CF₃NS: C, 49.41; H, 3.11; N, 4.80. Found: C, 49.43; H, 3.22; N,4.75.

Methyl4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-thiazol-5-yl]methyl]methoxy]cinnamate(5b)

In analogy to the procedure described in example 5a, chloromethyl 4b(0.331 g, 1.135 mmol) and Methyl 4-Hydroxycinnamate were treated withcesium carbonate in anhydrous acetonitrile to give 5b as a light yellowsolid (0.365 g, 0.842 mmol, 74.3%). TLC R_(f) (25% EtOAc/Hexane)=0.32.Mp 153-155° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 8.04 (2H, d, J=8.1 Hz),7.70 (2H, d, J=8.2 Hz), 7.68 (1H, d, J=16.0 Hz), 7.52 (2H, d, J=8.6 Hz),7.00 (2H, d, J=8.7 Hz), 6.36 (1H, d, J=16.0 Hz), 5.24 (2H, s), 3.8 (3H,s), 2.54 (3H, s). ¹³C NMR (CDCl₃, 150 MHz): δ (ppm) 167.79, 165.13,159.81, 152.49, 144.33, 136.67, 131.80 (q, ²J_(FC)=33 Hz), 129.96,128.20, 127.61, 126.75, 126.10 (m), 124.02 (q, ¹J_(FC)=270 Hz), 116.08,115.38, 62.29, 51.82, 15.57. Anal. Calcd for C₂₂H₁₈F₃NO₃S: C, 60.96; H,4.19; N, 3.23. Found: C, 60.79; H, 4.36; N, 3.15.

4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-thiazol-5-yl]methyl]methoxycinnamicAcid (BK-3-70)

In analogy to the procedure described in example BK-3-51, methyl ester5b (0.202 g, 0.466 mmol) was treated with 3N NaOH in 95% ethanol to giveBK-3-70 as a white solid (0.048 g, 0.114 mmol, 24.6%). TLC R_(f) (50%EtOAc/Hexane)=0.15. Mp 224-225° C. ¹H NMR (Acetone-d6, 600 MHz): δ ppm8.18 (2H, d, J=8.1 Hz), 7.85 (2H, d, J=8.2 Hz), 7.67 (2H, d, J=8.8 Hz),7.63 (1H, d, J=16.0 Hz), 7.13 (2H, d, J=8.8 Hz), 6.41 (1H, d, J=16.0Hz), 5.44 (2H, s), 2.53 (3H, s). ¹³C NMR (Acetone-d6, 150 MHz): δ ppm167.94, 164.82, 160.83, 153.28, 144.93, 137.90, 131.71 (q, ²J_(FC)=33Hz), 130.75, 129.46, 128.87, 127.50, 126.93 (m), 125.11 (q, ¹J_(FC)=270Hz), 117.15, 116.24, 62.85, 15.42. ¹⁹F NMR (Acetone-d6, 376 MHz): δ ppm−63.67 (3F, s). Anal. Calcd for C₂₁H₁₆F₃NO₃S: C, 60.14; H, 3.85; N,3.34. Found: C, 60.12; H, 3.85; N, 3.31.

Ethyl 4-Methyl-2-[3-(trifluoromethyl)phenyl]-thiazole-5-carboxylate (2c)

In analogy to the procedure described in example 2a,3-(trifluoromethyl)thiobenzamide 1c (2.00 g, 9.75 mmol) was treated withethyl-2-chloroacetoacetate in 95% ethanol to give 2c as a cream-coloredsolid (2.103 g, 6.677 mmol, 68.5%). TLC R_(f) (25% EtOAc/Hexane)=0.63.Mp 90-91° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 8.26 (1H, s), 8.14 (1H, d,J=7.86 Hz), 7.73 (1H, d, J=7.80 Hz), 7.60 (1H, dd, J₁=7.86 Hz, J₂=7.80Hz), 4.38 (2H, q, J=7.14 Hz), 2.81 (3H, s), 1.41 (3H, t, J=7.14 Hz). ¹³CNMR (CDCl₃, 150 MHz): δ (ppm) 167.94, 162.18, 161.34, 133.83, 131.80 (q,²J_(FC)=32.7 Hz), 130.03, 129.78, 127.48 (q, ³J_(FC)=3.5 Hz), 123.81 (q,³J_(FC)=271 Hz), 123.69 (q, ³J_(FC)=3.5 Hz), 122.84, 61.59, 17.65,14.46. Anal. Calcd for C₁₄H₁₂F₃NO₂S: C, 53.33; H, 3.84; N, 4.44. Found:C, 53.05; H, 3.93; N, 4.54.

4-Methyl-2-[3-(trifluoromethyl)phenyl]-thiazole-5-methanol (3c)

In analogy to the procedure described in example 3a, ethyl ester 2c(2.053 g, 6.516 mmol) was treated with 2M LiAlH₄ solution in THF to give3c as a yellow solid (1.273 g, 4.658 mmol, 71.5%). TLC R_(f) (25%EtOAc/Hexane)=0.16. Mp 58-60° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 8.19(1H, s), 8.07 (1H, d, J=7.8 Hz), 7.66 (1H, d, J=7.8 Hz), 7.56 (1H, t,J=7.8 Hz), 4.87 (2H, s), 2.49 (3H, s). ¹³C NMR (CDCl₃, 150 MHz): δ (ppm)164.43, 150.67, 134.31, 132.36, 131.61 (q, ²J_(FC)=32.5 Hz), 129.63,126.52 (q, ³J_(FC)=3.5 Hz), 123.92 (q, ¹J_(FC)=271 Hz), 123.19 (q,³J_(FC)=3.5 Hz), 56.95, 15.20.

5-Chloromethyl-4-methyl-2-[3-(trifluoromethyl)phenyl]thiazole (4c)

In analogy to the procedure described in example 4a, alcohol 3c (1.295g, 4.739 mmol) was treated with methanesulfonyl chloride andtriethylamine in dry DCM to give 4c as a light yellow solid (0.830 g,2.846 mmol, 60.1%). TLC R_(f) (25% EtOAc/Hexane)=0.61. Mp 43-44° C. ¹HNMR (CDCl₃, 600 MHz): δ ppm 8.19 (1H, s), 8.07 (1H, d, J=7.8 Hz), 7.68(1H, d, J=7.8 Hz), 7.57 (1H, t, J=7.8 Hz), 4.81 (2H, s), 2.51 (3H, s).¹³C NMR (CDCl₃, 150 MHz): δ (ppm) 165.09, 153.16, 134.21, 131.68 (q,²J_(FC)=33 Hz), 129.70, 129.67 128.75, 126.78 (q, ³J_(FC)=3.6 Hz),123.90 (q, ¹J_(FC)=271 Hz), 123.30 (q, ³J_(FC)=3.6 Hz), 37.37, 15.21.Anal. Calcd for C₁₂H₉CF₃NS: C, 49.41; H, 3.11; N, 4.80. Found: C, 49.46;H, 3.16; N, 4.91.

Ester4-[[4-methyl-2-[3-(trifluoromethyl)phenyl]-thiazol-5-yl]methyl]methoxycinnamate(5c)

In analogy to the procedure described in example 5a, chloromethyl 4c(0.472 g, 1.618 mmol) and Methyl 4-Hydroxycinnamate were treated withcesium carbonate in anhydrous acetonitrile to give 5c as a white solid(0.551 g, 1.270 mmol, 80.5%). TLC R_(f) (25% EtOAc/Hexane)=0.30. Mp125-127° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 8.19 (1H, s), 8.09 (1H, d,J=7.7 Hz), 7.68 (1H, d, J=7.8 Hz), 7.67 (1H, d, J=16.0 Hz), 7.56 (1H, t,J=7.8 Hz), 7.51 (2H, d, J=8.6 Hz), 6.99 (2H, d, J=8.7 Hz), 5.24 (2H, s),3.81 (3H, s), 2.54 (3H, s). ¹³C NMR (CDCl₃, 150 MHz): δ (ppm) 167.81,165.26, 159.79, 152.23, 144.34, 134.20, 131.66 (q, ²J_(FC)=32 Hz),129.96, 129.72, 129.67, 128.19, 127.36, 126.72 (q, ³J_(FC)=3.9 Hz),125.71 (q, ¹J_(FC)=270 Hz), 123.31 (q, ³J_(FC)=3.5 Hz), 116.06, 115.39,62.28, 51.81, 15.51. Anal. Calcd for C₂₂H₁₈F₃NO₃S (with 0.4H₂O mol pertarget): C, 59.97; H, 4.30; N, 3.18. Found: C, 59.66; H, 4.29; N, 3.07.

4-[[4-methyl-2-[3-(trifluoromethyl)phenyl]-thiazol-5-yl]methyl]methoxycinnamicAcid (BK-3-75)

In analogy to the procedure described in example BK-3-51, methyl ester5c (0.207 g, 0.477 mmol) was treated with 3N NaOH in 95% ethanol to giveBK-3-75 as a white solid (0.138 g, 0.329 mmol, 69.0%). TLC R_(f) (50%EtOAc/Hexane)=0.40. Mp 179.5-181° C. ¹H NMR (Acetone-d6, 600 MHz): δ ppm8.29 (1H, s), 8.23 (1H, d, J=7.8 Hz), 7.83 (1H, d, J=7.8 Hz), 7.76 (1H,t, J=7.8 Hz), 7.69 (2H, d, J=8.7 Hz), 7.65 (1H, d, J=16.0 Hz), 7.14 (2H,d, J=8.7 Hz), 6.43 (1H, d, J=16.0 Hz), 5.46 (2H, s), 2.54 (3H, s). ¹³CNMR (Acetone-d6, 150 MHz): δ ppm 167.93, 164.81, 160.85, 153.12, 145.02,135.37, 131.73 (q, ²J_(FC)=32 Hz), 131.14, 130.77, 130.70, 129.09,128.85, 127.27 (q, ³J_(FC)=3.3 Hz), 125.01 (q, ¹J_(FC)=270 Hz), 123.11(q, ³J_(FC)=3.5 Hz), 117.05, 116.24, 62.86, 15.42. ¹⁹F NMR (Acetone-d6,376 MHz): δ ppm −63.76 (s, 3F). Anal. Calcd for C₂₁H₁₆F₃NO₃S: C, 60.14;H, 3.85; N, 3.34. Found: C, 59.96; H, 3.89; N, 3.30.

Ethyl4-Methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]thiazole-5-carboxylate(2d)

In analogy to the procedure described in example 2a,3-fluoro-4-(trifluoromethyl)thiobenzamide 1d (1.606 g, 7.195 mmol) wastreated with ethyl-2-chloroacetoacetate in 95% ethanol to give 2d as acream-colored solid (1.657 g, 4.971 mmol, 69.1%). TLC R_(f) (25%EtOAc/Hexane)=0.72. Mp 101-102° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.86(1H, d, J=10.9 Hz), 7.82 (1H, d, J=7.7 Hz), 7.70 (1H, t, J=7.7 Hz), 4.40(2H, q, J=7.1 Hz), 2.80 (3H, s), 1.41 (3H, t, J=7.1 Hz). ¹³C NMR (CDCl₃,150 MHz): δ ppm 166.23, 161.97, 161.43, 160.16 (d, ¹J_(FC)=254 Hz),138.56 (d, ⁴J_(FC)=8.2 Hz), 128.16 (q, ²J_(FC)=3.9 Hz), 123.75, 122.39(q, ¹J_(FC)=271 Hz), 122.34 (d, ³J_(FC)=3.9 Hz), 120.20 (dq, ²J_(FC)=33Hz, ²J_(FC)=12 Hz), 115.07 (d, ²J_(FC)=23 Hz), 67.74, 17.62, 14.45. ¹⁹FNMR (CDCl₃, 376 MHz): δ ppm −61.74 (3F, s), −113.07 (1F, s). Anal. Calcdfor C₁₄H₁₁F₄NO₂S: C, 50.45; H, 3.33; N, 4.20. Found: C, 50.47; H, 3.32;N, 4.24.

5-Hydroxymethyl-4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]thiazole(3d)

In analogy to the procedure described in example 3a, ethyl ester 2d(4.640 g, 13.92 mmol) was treated with 2M LiAlH₄ solution in THF to give3d as a yellow solid (2.988 g, 10.26 mmol, 73.7%). TLC R_(f) (25%EtOAc/Hexane)=0.21 Mp 158-159° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.79(1H, d, J=11.2 Hz), 7.75 (1H, d, J=8.3 Hz), 7.65 (1H, t, J₁=7.6 Hz,J₂=7.7 Hz), 4.87 (2H, d, J=5.2 Hz), 2.48 (3H, s), 1.93 (1H, t, J=5.5Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 162.73, 160.16 (d, ¹J_(FC)=255 Hz),151.11, 139.20 (d, ⁴J_(FC)=8.2 Hz), 133.37, 127.98 (m), 122.53 (q,¹J_(FC)=271 Hz), 121.83 (d, ³J_(FC)=3.3 Hz), 119.17 (dq, ²J_(FC)=33 Hz,²J_(FC)=12 Hz), 114.48 (d, ²J_(FC)=23 Hz), 57.05, 15.27. ¹⁹F NMR (CDCl₃,376 MHz): δ ppm −61.81 (3F, s), −113.84 (1F, s). Anal. Calcd forC₁₂H₉F₄NOS: C, 49.49; H, 3.11; N, 4.81. Found: C, 49.52; H, 3.09; N,4.79.

5-Chloromethyl-4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]thiazole(4d)

In analogy to the procedure described in example 4a, alcohol 3d (1.502g, 5.157 mmol) was treated with methanesulfonyl chloride andtriethylamine in dry DCM to give 4d as a yellow oil (1.357 g, 4.382mmol, 85.0%). TLC R_(f) (25% EtOAc/Hexane)=0.68. ¹H NMR (CDCl₃, 600MHz): δ ppm 7.75 (2H, m), 7.65 (1H, m), 4.79 (2H, s), 2.50 (3H, s). ¹³CNMR (CDCl₃, 150 MHz): δ ppm 163.38, 161.02 (d, ¹J_(FC)=255 Hz), 159.32,153.52, 139.00 (d, ⁴J_(FC)=8.2 Hz), 129.83, 128.02 (q, ³J_(FC)=4 Hz),123.39 (q, ¹J_(FC)=270 Hz), 121.91 (m), 119.47 (dq, ²J_(FC)=33 Hz,²J_(FC)=12 Hz), 114.60 (d, ²J_(FC)=22 Hz), 37.15, 15.21. ¹⁹F NMR (CDCl₃,376 MHz): δ ppm −61.82 (3F, s), −113.62 (1F, s). Anal. Calcd forC₁₂H₉ClF₄NS: C, 46.54; H, 2.60; N, 4.52. Found: C, 46.61; H, 2.37; N,4.44.

Methyl4-[Oxo-[5-methylene-4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]-thiazole]]cinnamate(5d)

In analogy to the procedure described in example 5a, chloromethyl 4d(0.494 g, 1.595 mmol) and Methyl 4-Hydroxycinnamate were treated withcesium carbonate in anhydrous acetonitrile to give 5d as a white solid(0.614 g, 1.360 mmol, 85.3%). TLC R_(f)(25% EtOAc/Hexane)=0.46. Mp 180°C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.79 (1H, d, J=11 Hz), 7.76 (1H, d,J=8 Hz), 7.67 (1H, d, J=16.0 Hz), 7.66 (1H, m), 7.51 (2H, d, J=8.7 Hz),6.99 (2H, d, J=8.7 Hz), 6.35 (1H, d, J=16.0 Hz), 5.23 (2H, s), 3.80 (3H,s), 2.52 (3H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.77, 163.51, 161.00(d, ¹J_(FC)=254 Hz), 159.71, 152.65, 144.25, 139.14 (d, ⁴J_(FC)=8.4 Hz),129.89, 128.41, 128.26, 127.98 (q, ³J_(FC)=3.9 Hz), 123.40 (q,¹J_(FC)=270 Hz), 121.89 (d, ³J_(FC)=3 Hz), 119.48 (dq, ²J_(FC)=33 Hz,²J_(FC)=13 Hz), 116.13, 115.35, 114.64 (d, ²J_(FC)=22 Hz), 62.23, 51.81,15.55. Anal. Calcd for C₂₂H₁₇F₄NO₃S: C, 58.53; H, 3.80; N, 3.10. Found:C, 58.56; H, 3.83; N, 3.15.

4-[Oxo-[5-methylene-4-methyl-2-[3-fluoro-4-(trifluromethyl)phenyl]thiazole]]cinnamicAcid (JM-4-57)

In analogy to the procedure described in example BK-3-51, methyl ester5d (0.562 g, 1.245 mmol) was treated with 3N NaOH in 95% ethanol to giveJM-4-57 as a white solid (0.403 g, 0.921 mmol, 74.0%). TLC R_(f) (50%EtOAc/Hexane)=0.29. Mp 192-194° C. ¹H NMR (Acetone-d₆, 600 MHz): δ ppm7.97 (2H, t, J=11 Hz), 7.87 (1H, t, J=7.9 Hz), 7.68 (2H, d, J=8.7 Hz),7.65 (1H, d, J=16.0 Hz), 7.14 (2H, d, J=8.7 Hz), 6.43 (1H, d, J=16.0Hz), 5.46 (2H, s), 2.53 (3H, s). ¹³C NMR (Acetone-d₆, 150 MHz): δ ppm167.89, 163.30, 161.58 (d, ¹J_(FC)=254 Hz), 160.79, 153.41, 144.98,140.57 (d, ⁴J_(FC)=8.4 Hz), 130.77, 130.46, 129.14 (q, ³J_(FC)=3.9 Hz),128.91, 124.51 (q, ¹J_(FC)=270 Hz), 123.06 (d, ³J_(FC)=4 Hz), 119.11(dq, ²J_(FC)=33 Hz, ²J_(FC)=13 Hz), 117.10, 116.24, 114.89 (d,²J_(FC)=23 Hz), 62.86, 15.43. Anal. Calcd for C₂₁H₁₅F₄NO₃S: C, 57.66; H,3.46; N, 3.20. Found: C, 57.95; H, 3.48; N, 3.20.

2-(4-Bromophenyl)-1,3-dioxolane (6)

4-Bromobenzaldehyde (4.303 g, 23.26 mmol) was dissolved in anhydroustoluene (50 mL) and ethylene glycol (3.80 mL, 69.18 mmol) was addedfollowed by p-toluenesulfonic acid monohydrate (0.303 g, 1.59 mmol). Themixture was heated to a vigorous reflux set at 140° C. in a Dean-Starkapparatus and stirred at that temperature for 2 days. The mixture wasallowed to cool and was poured into a 75 mL saturated NaHCO₃ solutionand extracted with 40 mL toluene. The organic phase was collected andwashed with water twice, dried with Na₂SO₄, and concentrated underreduced pressure. The resulting crude mixture was purified using columnchromatography to give 6 as white solid (2.787 g, 12.17 mmol, 52.3%).TLC R_(f) (25% EtOAc/Hexane)=0.55. Mp 34-35° C. ¹H NMR (CDCl₃, 600 MHz):δ (ppm) 7.52 (2H, d, J=8.4 Hz), 7.36 (2H, d, J=8.4 Hz), 5.78 (1H, s),4.10 (2H, m), 4.02 (2H, m). ¹³C NMR (CDCl₃, 150 MHz): δ (ppm) 137.29,131.63, 128.30, 123.33, 103.19, 65.43. Anal. Calcd for C₉H₉O₂Br: C,47.19; H, 3.96; N, 0.00. Found: C, 47.00; H, 3.97; N, 0.00.

2-[4-Thio-[5-methylene-4-methyl-2-phenylthiazole]phenyl]-1,3-dioxolane(7a)

Acetal 6 (0.934 g, 4.077 mmol) was dissolved in THF (15 mL) and cooledto −78° C. A t-BuLi solution in THF (1.7 M, 4.8 mL, 8.55 mmol) was addedslowly and the reaction was stirred for 2 hours. Sulfur (0.131 g, 4.078mmol) was suspended in THF (9 mL) and added to the reaction at −78° C.The mixture was stirred at r.t. for 1.5 hours and was then cooled to 0°.Thiazole 4a (0.918 g, 4.103 mmol) was dissolved in THF (15 mL) and addedto the reaction mixture. The reaction mixture was allowed to warm tor.t. and stirred for an additional 2 hours. The mixture was quenchedwith aqueous NH₄Cl and the organic phase was separated. The aqueousphase was extracted using two portions of EtOAc and the organic phaseswere combined and washed with water, brine, and dried over Na₂SO₄. Afterevaporation of the solvent, a crude product 7a was isolated as a stickyyellow solid. Attempts to purify the product using column chromatographywere unsuccessful and the material was moved to the next step (0.941 g,2.546 mmol, 62.5%). TLC R_(f) (25% EtOAc/Hexane)=0.23.

4-Thio-[5-methylene-4-methyl-2-phenylthiazole]benzaldehyde (8a)

Crude acetal 7a (0.476 g, 1.288 mmol) was dissolved in THF (15 mL) and3N HCl (5 mL) was added. The reaction mixture was stirred at r.t. for 2hours and was concentrated under reduced pressure. The residue wasneutralized with 1N NaOH and extracted with EtOAc. The organic extractwas washed with water, brine, and dried with Na₂SO₄. After evaporationof the solvent, the product was purified with column chromatographyusing a gradient of 10-20% EtOAc/Hexane. The purified product 8a wascollected as a yellow solid (0.302 g, 0.928 mmol, 72.0%). TLC R_(f) (25%EtOAc/Hexane)=0.35. Mp 116-117° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 9.95(1H, s), 7.86 (2H, m), 7.80 (2H, d, J=8.3 Hz), 7.43 (2H, d, J=8.3 Hz),7.41 (3H, m), 4.37 (2H, s), 2.43 (3H, s). ¹³C NMR (CDCl₃, 150 MHz): δppm 191.34, 165.94, 151.23, 144.55, 134.30, 133.51, 130.28, 130.17,129.04, 128.34, 127.31, 126.42, 29.28, 15.34. Anal. Calcd forC₁₈H₁₅NOS₂: C, 66.43; H, 4.65; N, 4.30. Found: C, 66.29; H, 4.53; N,4.19.

Methyl 4-[Thio-[5-methylene-4-methyl-2-phenylthiazole]]cinnamate (9a)

Aldehyde 8a (0.251 g, 0.771 mmol) and Methyl(triphenylphosphoranylidene)acetate (0.291 g, 0.870 mmol) were dissolvedin THF (6 mL) and stirred at 60° C. for 2 days. The reaction mixture wasconcentrated and the resulting residue was taken up into EtOAc andwashed with water, brine, and dried with Na₂SO₄. After evaporation ofthe solvent, the product was purified with column chromatography using agradient of 5-15% EtOAc/Hexane. The product collected from the columnwas recrystallized using 95% EtOH to give 9a as a light yellow solid(0.244 g, 0.640 mmol, 83.1%). TLC R_(f) (25% EtOAc/Hexane)=0.36. Mp102-103° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.87 (2H, m), 7.63 (1H, d,J=16.0 Hz), 7.44 (2H, d, J=8.2 Hz), 7.41 (3H, m), 7.34 (2H, d, J=8.3Hz), 6.41 (1H, d, J=16.0 Hz), 4.27 (2H, s), 3.80 (3H, s), 2.35 (3H, s).¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.47, 143.99, 137.99, 133.19, 130.50,130.32, 129.10, 128.86, 128.73, 128.47, 127.35, 126.62, 126.53, 118.09,51.93, 30.43, 15.08. Anal. Calcd for C₁₈H₁₅NOS₂: C, 66.11; H, 5.02; N,3.67. Found: C, 66.05; H, 4.87; N, 3.56.

4-[Thio-[5-methylene-4-methyl-2-phenylthiazole]]cinnamic Acid (BK-3-95)

Methyl ester 9a (0.200 g, 0.524 mmol) was dissolved in 95% EtOH (15 mL)using heat. The mixture was cooled to r.t. and 3N NaOH was added. Thereaction mixture was stirred for 24 hours and was concentrated underreduced pressure. The resulting residue was taken up into EtOAc andwashed with acidified water (HCl, pH=3), brine, and dried with Na₂SO₄.After evaporation of the solvent, the product was purified by columnchromatography using a gradient of 25-100% EtOAc/Hexane. The productcollected from the column was recrystallized using 95% EtOH to giveBK-3-95 as an off-white solid (0.089 g, 0.243 mmol, 46.4%). TLCR_(f)(50% EtOAc/Hexane)=0.33. Mp 192.5-193.5° C. ¹H NMR (CDCl₃, 600MHz): δ ppm 7.90 (2H, m), 7.65-7.61 (3H, m), 7.45 (5H, m), 6.51 (1H, d,J=16.0 Hz), 4.52 (2H, s), 2.35 (3H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm167.47, 165.27, 151.85, 144.41, 139.06, 134.47, 133.69, 130.67, 130.46,129.77, 129.46, 126.67, 119.15, 15.09. Anal. Calcd for C₁₈H₁₅NOS₂(0.2H₂O mol per target): C, 65.37; H, 4.66; N, 3.81. Found: C, 64.64; H,4.57; N, 3.72.

2-[4-Thio-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]phenyl]-1,3-dioxolane(7b)

Acetal 6 (0.909 g, 3.968 mmol) was dissolved in THF (15 mL) and cooledto −78° C. A t-BuLi solution in THF (1.7 M, 4.7 mL, 7.99 mmol) was addedslowly and the reaction was stirred for 2 hours. Sulfur (0.130 g, 4.053mmol) was suspended in THF (12 mL) and added to the reaction at −78° C.The mixture was stirred at r.t. for 1.5 hours and was then cooled to 0°C. Thiazole 4b (1.150 g, 3.942 mmol) was dissolved in THF (15 mL) andadded to the reaction mixture. The reaction mixture was allowed to warmto r.t. and stirred for an additional 2 hours. The mixture was quenchedwith aqueous NH₄Cl and the organic phase was separated. The aqueousphase was extracted using two portions of EtOAc and the organic phaseswere combined and washed with water, brine, and dried over Na₂SO₄. Afterevaporation of the solvent, a crude product was isolated as a stickyyellow solid. The crude product was purified by column chromatographyusing a 5-20% EtOAc/Hexane gradient to give 7b as a yellow solid (0.658g, 1.504 mmol, 38.2%). TLC R_(f) (25% EtOAc/Hexane)=0.33.Mp 57-61° C. ¹HNMR (CDCl₃, 600 MHz): δ ppm 7.98 (2H, d, J=8.1 Hz), 7.66 (2H, d, J=8.1Hz), 7.42 (2H, d, J=8.2 Hz), 7.38 (2H, d, J=8.4 Hz), 5.78 (1H, s), 4.24(2H, s), 4.12 (2H, m), 4.04 (2H, m), 2.31 (3H, m). ¹³C NMR (CDCl₃, 150MHz): δ ppm 163.49, 151.42, 137.35, 136.74, 135.84, 131.47 (q,²J_(FC)=32 Hz), 131.09, 130.36, 127.39, 126.56, 125.99 (m), 124.04,103.33, 65.46, 30.98, 15.11. Anal. Calcd for C₂₁H₁₈NO₂S₂ (with 0.4H₂Omol per target): C, 56.72; H, 4.26; N, 3.15. Found: C, 56.50; H, 4.00;N, 3.32.

4-Thio-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]benzaldehyde(8b)

Acetal 7b (0.589 g, 1.346 mmol) was dissolved in THF (20 mL) and 3N HCl(5 mL) was added. The reaction mixture was stirred at r.t. for 2 hoursand was concentrated under reduced pressure. The residue was neutralizedwith 1N NaOH and extracted with EtOAc. The organic extract was washedwith water, brine, and dried with Na₂SO₄. After evaporation of thesolvent, the product was purified with column chromatography using agradient of 5-20% EtOAc/Hexane. The purified product 8b was collected asa yellow solid (0.297 g, 0.754 mmol, 56.0%). TLC R_(f) (25%EtOAc/Hexane)=0.36. Mp 77-79° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 9.94(1H, s), 7.96 (2H, d, J=8.1 Hz), 7.79 (2H, d, J=8.5 Hz), 7.65 (2H, d,J=8.2 Hz), 7.43 (2H, d, J=8.3 Hz), 4.36 (2H, s), 2.43 (3H, s). ¹³C NMR(CDCl₃, 150 MHz): δ ppm 191.28, 163.85, 151.76, 144.21, 136.58, 134.39,131.65 (q, ²J_(FC)=32 Hz), 130.30, 128.94, 128.37, 126.57, 126.04 (m),123.99 (q, ¹J_(FC)=271 Hz), 29.19, 15.32. Anal. Calcd for C₁₈H₁₅NOS₂: C,58.00; H, 3.59; N, 3.56. Found: C, 57.83; H, 3.67; N, 3.63.

Methyl4-[Thio-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]-thiazole]]cinnamate(9b)

Aldehyde 8b (0.248 g, 0.629 mmol) and Methyl(triphenylphosphoranylidene)acetate (0.238 g, 0.712 mmol) were dissolvedin THF (6 mL) and stirred at 40° C. for 2 days. The reaction mixture wasconcentrated and the resulting residue was taken up into EtOAc andwashed with water, brine, and dried with Na₂SO₄. After evaporation ofthe solvent, the product 9b was purified with column chromatographyusing a gradient of 5-15% EtOAc/Hexane and collected as a light yellowsolid (0.201 g, 0.447 mmol, 71.1%). TLC R_(f) (25% EtOAc/Hexane)=0.44.Mp 121-122° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.98 (2H, d, J=8.1 Hz),7.65 (3H, m), 7.45 (2H, d, J=8.2 Hz), 7.35 (2H, d, J=8.3 Hz), 6.42 (1H,d, J=16.0 Hz), 4.28 (2H, s), 3.81 (3H, s), 2.36 (3H, s). ¹³C NMR (CDCl₃,150 MHz): δ ppm 167.43, 163.68, 151.50, 143.91, 137.80, 136.62, 133.27,131.61 (q, ²J_(FC)=32.5 Hz), 130.53, 129.90, 128.74, 126.58, 126.03 (m),124.01 (q, ¹J_(FC)=270 Hz), 118.16, 51.93, 30.39, 15.19. Anal. Calcd forC₁₈H₁₅NOS₂: C, 58.78; H, 4.04; N, 3.12. Found: C, 58.98; H, 4.05; N,3.13.

4-Thio-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]cinnamicAcid (BK-4-04)

To a stirred solution of methyl ester 9b (0.178 g, 0.396 mmol) in 95%Ethanol (12 mL) was added dropwise 3N NaOH (1 mL). After 20 hours, themixture was concentrated and the resulting residue was suspended inethyl acetate and washed with acidified water (pH=3, HCl). The organicphase was then washed with water and brine, dried with Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography andrecrystallized with 95% Ethanol to give the product BK-4-04 as a lightyellow solid (0.119 g, 0.273 mmol, 68.9%). TLC R_(f) (50%EtOAc/Hexane)=0.54. Mp 217° C. ¹H NMR (Acetone-d6, 600 MHz): δ ppm 8.11(2H, d. J=8.1 Hz), 7.80 (2H, d, J=8.1 Hz), 7.64 (3H, m), 7.47 (2H, d,J=8.5 Hz), 6.52 (1H, d, J=16.1 Hz), 4.55 (2H, s), 2.39 (3H, s). ¹³C NMR(Acetone-d6, 150 MHz): δ ppm 172.99, 167.62, 163.35, 152.54, 144.54,128.94, 137.98, 133.89, 131.69 (q, ²J_(FC)=32 Hz), 130.64, 129.61,129.45, 127.31, 126.87 (m), 125.13 (q, ¹J_(FC)=270 Hz), 119.25, 15.21.¹⁹F NMR (Acetone-d6, 376 MHz): δ ppm −63.67 (s, 3F). Anal. Calcd. forC₂₁H₁₆F₃NO₂S₂: C, 57.92; H, 3.70; N, 3.22. Found: C, 57.80; H, 3.66; N,3.29.

2-[4-Thio-[5-methylene-4-methyl-2-[3-(trifluoromethyl)phenyl]thiazole]phenyl]-1,3-dioxolane(7c)

Acetal 6 (1.079 g, 4.710 mmol) was dissolved in THF (15 mL) and cooledto −78° C. A t-BuLi solution in THF (1.7 M, 5.6 mL, 9.52 mmol) was addedslowly and the reaction was stirred for 2 hours. Sulfur (0.176 g, 5.488mmol) was suspended in THF (10 mL) and added to the reaction at −78° C.The mixture was stirred at r.t. for 1.5 hours and was then cooled to 0°C. Thiazole 4c (1.3.90 g, 4.765 mmol) was dissolved in THF (17 mL) andadded to the reaction mixture. The reaction mixture was allowed to warmto r.t. and stirred for an additional 2 hours. The mixture was quenchedwith aqueous NH₄Cl and the organic phase was separated. The aqueousphase was extracted using two portions of EtOAc and the organic phaseswere combined and washed with water, brine, and dried over Na₂SO₄. Afterevaporation of the solvent, a crude product 7c was isolated as an orangeoil. Attempts to purify the product using column chromatography wereunsuccessful and the material was moved to the next step (0.604 g, 1.381mmol, 29.3%). TLC R_(f) (25% EtOAc/Hexane)=0.31.

4-Thio-[5-methylene-4-methyl-2-[3-(trifluromethyl)phenyl]thiazole]benzaldehyde(8c)

Crude acetal 7c (0.604 g, 1.381 mmol) was dissolved in THF (20 mL) and3N HCl (5 mL) was added. The reaction mixture was stirred at r.t. for2.5 hours and was concentrated under reduced pressure. The residue wasneutralized with 1N NaOH and extracted with EtOAc. The organic extractwas washed with water, brine, and dried with Na₂SO₄. After evaporationof the solvent, the product was purified with column chromatographyusing a gradient of 10-20% EtOAc/Hexane. The purified product 8c wascollected as a yellow solid (0.275 g, 0.698 mmol, 50.6%). Elementalanalysis was completed after NMR experiments leading to CDCl₃contaminant. TLC R_(f) (25% EtOAc/Hexane)=0.40. Mp 89-91° C. ¹H NMR(CDCl₃, 600 MHz): δ ppm 9.95 (1H, s), 8.15 (1H, s), 8.02 (1H, d, J=7.8Hz), 7.81 (2H, d, J=8.5 Hz), 7.65 (1H, d, J=7.8 Hz), 7.54 (1H, d, J=7.8Hz), 7.44 (2H, d, J=8.3 Hz), 4.37 (2H, s), 2.44 (3H, s). ¹³C NMR (CDCl₃,150 MHz): δ ppm 191.32, 163.96, 151.64, 144.24, 134.40, 134.27, 131.60(q, ²J_(FC)=33 Hz), 130.33, 129.60, 129.54, 128.65, 128.39, 126.54 (m),123.90 (q, ¹J_(FC)=271 Hz), 123.13, 29.22, 15.34. Anal. Calcd forC₁₉H₁₄F₃NOS₂ (with 1.0H₂O and 0.1 CDCl₃ mol per target): C, 58.00; H,3.59; N, 3.56. Found: C, 54.11; H, 3.57; N, 3.41.

Methyl4-[Thio-[5-methylene-4-methyl-2-[3-(trifluoromethyl)phenyl]-thiazole]]cinnamate(9c)

Aldehyde 8c (0.239 g, 0.607 mmol) and Methyl(triphenylphosphoranylidene)acetate (0.228 g, 0.682 mmol) were dissolvedin THF (6 mL) and stirred at 60° C. for 2 days. The reaction mixture wasconcentrated and the resulting residue was taken up into EtOAc andwashed with water, brine, and dried with Na₂SO₄. After evaporation ofthe solvent, the product was purified with column chromatography using10% EtOAc/Hexane and collected 9c as a light yellow solid (0.130 g,0.289 mmol, 47.6%). TLC R_(f) (25% EtOAc/Hexane)=0.53. Mp 142-143° C. ¹HNMR (CDCl₃, 600 MHz): δ ppm 8.14 (1H, s), 8.01 (1H, d, J=7.9 Hz), 7.65(2H, m), 7.53 (1H, t, J=7.9 Hz), 7.45 (2H, d, J=8.2 Hz), 7.34 (2H, d,J=8.3 Hz), 6.42 (1H, d, J=16.0 Hz), 4.28 (2H, s), 3.81 (3H, s), 2.35(3H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.44, 163.72, 151.47, 143.94,137.87, 134.40, 133.24, 131.58 (q, ²J_(FC)=33 Hz), 130.51, 129.56,129.53, 129.52, 128.74, 126.43 (m), 123.93 (q, ¹J_(FC)=271 Hz), 123.10(m), 118.13, 51.92, 30.40, 15.22. Anal. Calcd for C₁₈H₁₅NOS₂: C, 58.78;H, 4.04; N, 3.12. Found: C, 58.49; H, 3.90; N, 3.18.

4-Thio-[5-methylene-4-methyl-2-[3-(trifluoromethyl)phenyl]thiazole]cinnamicAcid (BK-4-37)

To a stirred solution of methyl ester 9c (0.120 g, 0.267 mmol) in 95%Ethanol (5 mL) and THF (5 mL) was added dropwise 3N NaOH (1 mL). After20 hours, the mixture was concentrated and the resulting residue wastaken up into EtOAc and washed with acidic water (HCl, pH=3), brine,dried with Na₂SO₄, and concentrated. After evaporation of the solvent,the product was purified using column chromatography and recrystallizedwith 95% Ethanol to give the product BK-4-37 as a light yellow solid(0.082 g, 0.188 mmol, 70.7%). TLC R_(f) (50% EtOAc/Hexane)=0.51. Mp150-151° C. ¹H NMR (Acetone-d6, 600 MHz): δ ppm 8.21 (1H, s), 8.13 (1H,d. J=7.8 Hz), 7.78 (2H, d, J=7.8 Hz), 7.71 (1H, t, J=7.8 Hz), 7.64 (3H,m), 7.46 (2H, d, J=8.3 Hz), 6.52 (1H, d, J=16.0 Hz), 4.54 (2H, s), 2.38(3H, s). ¹³C NMR (Acetone-d6, 150 MHz): δ ppm 167.64, 163.37, 152.37,144.54, 138.95, 135.43, 133.89, 131.69 (q, ²J_(FC)=33 Hz), 131.22,131.08, 130.65, 130.54, 129.60, 127.05 (m), 125.00 (q, ¹J_(FC)=270 Hz),122.92 (m), 119.25, 15.18. ¹⁹F NMR (Acetone-d6, 376 MHz): δ ppm −63.79(3F, s). Anal. Calcd for C₂₁H₁₆F₃NO₂S₂: C, 57.92; H, 3.70; N, 3.22.Found: C, 57.81; H, 3.72; N, 3.23.

2-[4-Thio-[5-methylene-4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]thiazole]phenyl-1,3-dioxolane(7d)

Acetal 6 (0.915 g, 3.99 mmol) was dissolved in THF (15 mL) and cooled to−78° C. A t-BuLi solution in THF (1.7 M, 4.7 mL) was added slowly andthe reaction was stirred for 2 hours. Sulfur (0.129 g, 4.022 mmol) wassuspended in THF (12 mL) and added to the reaction at −78° C. Themixture was stirred at r.t. then cooled to 0° C. and thiazole 4d (0.9589g, 3.29 mmol) was added in THF (15 mL). After 20 minutes the reactionwas allowed to warm to r.t. and was stirred for an additional 1 hour.The mixture was quenched with NH₄Cl and the organic phase was separated.The aqueous phase was then extracted using two portions of EtOAc. Thecombined extract was washed with water and brine then dried over Na₂SO₄.After evaporation of the solvent, the product was purified with columnchromatography using a 0-20% EtOAc/Hexane gradient to give the product7d as an off-white solid (0.3539 g, 0.776 mmol, 19%). TLC R_(f) (25%EtOAc/Hexane)=0.40. Mp 105-107° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.73(1H, m), 7.70 (1H, m), 7.62 (1H, t, J=7.5), 7.40 (2H, m), 7.37 (2H, m),5.77 (1H, s), 4.22 (2H, s), 4.10 (2H, m), 4.04 (2H, m), 2.30 (3H, s).¹³C NMR (CDCl₃, 150 MHz): δ ppm 161.79, 160.85 (d, ¹J_(FC)=255 Hz),151.54, 139.07 (d, ⁴J_(FC)=8.2 Hz), 137.34, 135.53, 131.05, 127.77 (d,³J_(FC)=3.9 Hz), 127.32, 122.42 (q, ¹J_(FC)=270 Hz), 121.61 (d,³J_(FC)=3.3 Hz), 118.90 (dq, ²J_(FC)=33 Hz, ²J_(FC)=12 Hz), 114.27, (d,¹J_(FC)=23 Hz), 103.20, 65.36, 30.83, 14.99. Anal. Calcd forC₂₁H₁₇F₄NO₂S₂: C, 55.38; H, 3.76; N, 3.08. Found: C, 55.41; H, 3.65; N,3.20.

4-Thio-[5-methylene-4-methyl-2-[3-fluoro-4-(trifluromethyl)phenyl]thiazole]benzaldehyde(8d)

Acetal 7d (0.354 g, 0.7770 mmol) was dissolved in THF (12 mL) and 3N HCl(3 mL) was added. The mixture was stirred for 3 hours at roomtemperature. Sample was concentrated under reduced pressure andneutralized with 1N NaOH. The mixture was then taken into EtOAc, washedwith water, brine, and dried with Na₂SO₄. After evaporation of thesolvent, the crude product was purified with column chromatography usinga 5-20% EtOAc/Hexane gradient to give the desired product 8d as anoff-white solid (0.2443 g, 0.593 mmol, 76%). TLC R_(f)(25%EtOAc/Hexane)=0.33. Mp 122-123° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 9.91(1H, s), 7.76 (2H, d, J=8.4 Hz), 7.69 (1H, d, J=11.2 Hz), 7.65 (1H, d,J=8.3 Hz), 7.59 (1H, t, J=7.6 Hz), 7.39 (2H, d, J=8.4 Hz), 4.32 (2H, s),2.39 (3H, s), 1.50 (3H, s). C NMR (CDCl₃, 150 MHz): δ ppm 191.15,162.16, 160.0 (d, ¹J_(FC)=256 Hz), 151.87, 143.86, 138.88 (d,¹J_(FC)=8.3 Hz), 134.37, 130.22, 128.34, 127.82 (d, ³J_(FC)=4.2 Hz),122.36 (q, ¹J_(FC)=270 Hz), 121.64, 119.11 (dq, ²J_(FC)=33 Hz,²J_(FC)=13 Hz), 114.31 (d, ¹J_(FC)=22 Hz), 29.05, 15.20. Anal. Calcd forC₁₉H₁₃F₄NOS₂: C, 55.47; H, 3.18; N, 3.40. Found: C, 55.64; H, 3.35; N,3.42.

Methyl4-[Thio-[5-methylene-4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]-thiazole]]cinnamate(9d)

Aldehyde 8d (0.244 g, 0.594 mmol) was dissolved in THF under inert gasand Methyl (triphenylphosphoranylidene)acetate (0.216 g, 0.646 mmol) wasadded. Reaction was heated to 74° C. and stirred for 2 days. The mixturewas concentrated and the resulting residue was taken up into EtOAc andwashed with water, brine, and dried with Na₂SO₄. After evaporation ofthe solvent, the crude product was purified with column chromatographyusing a 5-20% gradient to give the desired product 9d as a white solid(56.1 mg, 0.12 mmol, 20%). TLC R_(f)(25% EtOAc/Hexane)=0.40. Mp 121-123°C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.72 (1H, d, J=11.2 Hz), 7.69 (1H, d,J=8.3 Hz), 7.63 (2H, m), 7.44 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.3 Hz),6.40 (1H, d, J=16.0 Hz), 4.27 (2H, s), 3.80 (3H, s), 2.34 (3H, s). ¹³CNMR (CDCl₃, 150 MHz): δ ppm 167.28, 161.95, 160.01 (d, ¹J_(FC)=254 Hz),151.64, 143.74, 138.95 (d, ¹J_(FC)=8.3 Hz), 137.48, 133.23, 130.71,130.46, 128.64, 127.8 (d, ³J_(FC)=4.0 Hz), 122.38 (d, ¹J_(FC)=271 Hz),121.63, 118.90 (dq, ²J_(FC)=33 Hz, ²J_(FC)=13 Hz), 118.11, 114.27 (d,²J_(FC)=23 Hz), 51.81, 30.02, 15.05. Anal. Calcd for C₂₂H₁₇F₄NO₂S₂: C,56.62; H, 3.67; N, 3.00. Found: C, 56.54; H, 3.73; N, 3.02.

4-Thio-[5-methylene-4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]thiazole]cinnamicAcid (JF-4-80)

Methyl ester 9d (0.053 g, 0.113 mmol) was dissolved in 95% EtOH (10 mL)with heat. Mixture was allowed to cool to room temperature before 3NNaOH (1 mL) was added. Mixture was stirred overnight and was thenconcentrated under reduced pressure. Residue was taken into EtOAc andwas washed with acidified water (HCl, pH=3), water, brine, and driedwith Na₂SO₄. Sample recrystallized with 95% ethanol to give JF-4-80 as awhite solid (20 mg, 0.0441 mmol, 38%). TLC R_(f) (25%EtOAc/Hexane)=0.20. Mp 180-182° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.88(2H, m), 7.84 (1H, m), 7.64 (3H, m), 7.47 (2H, m), 6.51 (1H, d, J=15.9Hz), 4.56 (2H, s), 2.39 (3H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 166.69,160.96, 159.88 (d, ¹J_(FC)=256 Hz), 151.87, 143.63, 139.71 (d,⁴J_(FC)=8.8 Hz), 137.89, 133.05, 131.86, 129.78, 128.73, 128.17 (d,³J_(FC)=4.2 Hz), 122.73 (d, ¹J_(FC)=269 Hz), 121.99, 118.37, 117.95 (dq,²J_(FC)=33 Hz, ²J_(FC)=12 Hz), 113.69 (d, ²J_(FC)=23 Hz), 14.30. Anal.Calcd for C₂₁H₁₅F₄NO₂S₂: C, 55.62; H, 3.33; N, 3.09. Found: C, 55.35; H,3.44; N, 3.04.

Ethyl 4-(N-tert-butoxycarbonyl)aminocinnamate (10)

Ethyl 4-aminocinnamate (1.270 g, 6.641 mmol) and di-tert-butyldicarbonate (1.480 g, 6.781 mmol) were dissolved in THF (20 mL) underinert gas and heated to reflux at 65° C. overnight. The mixture wascooled to room temperature and concentrated under reduced pressure. Theresulting residue was taken up into EtOAc and washed with sat. NaHCO₃,water, brine, dried with Na₂SO₄, and concentrated. The crude sample waspurified using column chromatography to give the desired product 10alight orange solid (1.200 g, 4.122 mmol, 62.1%). TLC R_(f) (25%EtOAc/Hexane)=0.46. Mp 93-96° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.63(1H, d, J=16.0 Hz), 7.47 (2H, d, J=8.6 Hz), 7.39 (2H, d, J=8.5 Hz), 6.59(1H, s), 6.34 (1H, d, J=16.0 Hz), 4.26 (2H, q, J=7.1 Hz), 1.53 (9H, s),1.34 (3H, t, J=7.1 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ (ppm) 167.36,152.43, 144.17, 140.37, 129.19, 118.39, 116.62, 81.16, 60.51, 28.40,14.46. Anal. Calcd for C₁₆H₂₁NO₄: C, 65.96; H, 7.27; N, 4.81. Found: C,65.81; H, 7.42; N, 4.93.

Ethyl4-[N-(tert-Butoxycarbonyl)-N-[(5-methylene-4-methyl-2-phenyl)thiazole]]aminocinnamate(11a)

Ethyl 4-(N-tert-Butoxycarbonyl)aminocinnamate 10 (1.336 g, 4.586 mmol),thiazole 4a (1.027 g, 4.590 mmol), and NaI (0.690 g, 4.603 mmol) weredissolved in anhydrous DMF (30 mL) under inert gas and cooled in an icebath. NaH (60% dispersion in mineral oil, 0.281 g, 7.025 mmol) wascarefully added to the reaction mixture by briefly exposing the systemto air. The reaction mixture was stirred for 3 hours at room temperatureand quenched with a 50% dilution of sat. NaHCO₃. The mixture wasextracted with three portions of ether which were combined, washed withbrine, dried with Na₂SO₄, and concentrated. The crude material waspurified by column chromatography using a gradient of 100% hexane to 25%EtOAc/hexane to give the desired product 1a as a yellow oil (1.488 g,3.109 mmol, 67.8%). TLC R_(f) (25% EtOAc/Hexane)=0.39. ¹H NMR (CDCl₃,600 MHz): δ ppm 7.87 (2H, m), 7.64 (1H, d, J=16.0 Hz), 7.46 (2H, d,J=8.5 Hz), 7.39 (3H, m), 7.15 (2H, bd, J=8.0 Hz), 6.39 (1H, d, J=16.0Hz), 4.94 (2H, s), 4.25 (2H, q, J=7.1 Hz), 2.19 (3H, s), 1.47 (9H, s),1.32 (3H, t, J=7.1 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.00, 166.24,154.12, 150.93, 143.69, 143.49, 133.67, 132.70, 130.02, 128.99, 128.71,128.16, 127.49, 126.41, 118.57, 81.61, 60.65, 45.87, 28.42, 15.13,14.43. Anal. Calcd for C₂₇H₃₀N₂O₄S (with 0.2H₂O mol per target): C,67.25; H, 6.35; N, 5.81. Found: C, 67.02; H, 6.55; N, 5.58.

Ethyl 4-[N-[5-Methylene-4-methyl-2-phenylthiazole]]aminocinnamate (12a)

BOC protected amine 11a (1.354 g, 2.749 mmol) was dissolved in anhydrousDCM (15 mL) and cooled in an ice bath. Trifluoroacetic acid (3 mL) wasadded slowly and the mixture was stirred at room temperature for 3hours. The reaction mixture was then washed with a chilled saturatedNaHCO₃ solution, water, brine, and dried with Na₂SO₄. After filtrationand evaporation of the solvent, the crude product was purified withcolumn chromatography using a gradient of 10% EtOAc/hexane to 25%EtOAc/hexane. The purified product 12a was collected as a yellow solid(0.810 g, 2.140 mmol, 77.8%). TLC R_(f) (25% EtOAc/Hexane)=0.23. Mp112-113° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.86 (2H, m), 7.60 (1H, d,J=15.9 Hz), 7.39 (5H, m), 6.63 (2H, d, J=8.6 Hz), 6.23 (1H, d, J=15.8Hz), 4.47 (2H, s), 4.37 (1H, bs), 4.23 (2H, q, J=7.1 Hz), 2.48 (3H, s),1.32 (3H, t, J=7.1 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.83, 165.86,150.16, 149.10, 144.89, 133.63, 130.02, 129.49, 129.01, 126.38, 124.65,113.75, 113.00, 60.30, 40.19, 15.44, 14.50. Anal. Calcd for C₂₂H₂₂N₂O₂S:C, 69.81; H, 5.86; N, 7.40. Found: C, 69.57; H, 5.88; N, 7.53.

4-[N-[5-Methylene-4-methyl-2-phenylthiazole]]aminocinnamic Acid(BK-3-91)

Methyl ester 12a (0.721 g, 1.905 mmol) was dissolved in a mixture of THF(20 mL) and 95% ethanol (10 mL). A 3N NaOH solution (3 mL) was added andthe reaction mixture was stirred for 24 hours. The reaction was found tobe incomplete as determined by TLC and additional 3N NaOH (3 mL) wasadded. The mixture was stirred for an additional 24 hours (48 hourstotal) and was neutralized and then acidified with 1N HCl (to pH=3).Organic solvents were removed under reduced pressure and the residue wasextracted with EtOAc. The organic extract was washed with brine, driedwith Na₂SO₄, and concentrated. The crude material was purified by columnchromatography using a 25% EtOAc/Hexane to 30% EtOAc/Hexane gradientsupplemented with dropwise amounts of acetic acid to give the desiredproduct BK-3-91 as a yellow solid (0.308 g, 0.879 mmol, 46.1%). TLCR_(f) (50% EtOAc/Hexane)=0.15. Mp 205-207° C. ¹H NMR (Acetone-d6, 600MHz): δ ppm 10.41 (1H, bs), 7.91 (2H, m), 7.56 (2H, d, J=15.9 Hz), 7.44(5H, m), 6.76 (2H, d, J=8.6 Hz), 6.23 (1H, d, J=15.9 Hz), 6.16 (1H, bs),4.61 (2H, s), 2.47 (3H, s). ¹³C NMR (Acetone-d6, 150 MHz): δ ppm 168.35,165.07, 151.06, 150.59, 146.12, 134.77, 132.01, 130.74, 130.58, 129.83,126.70, 124.32, 113.57, 113.46, 40.11, 15.39. Anal. Calcd forC₂₀H₁₈N₂O₂S: C, 68.55; H, 5.18; N, 7.99. Found: C, 68.46; H, 5.20; N,8.06.

Ethyl4-[N-(tert-Butoxycarbonyl)-N-[(5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamate(11b)

Ethyl ester 10 (1.342 g, 4.606 mmol), thiazole 4b (1.345 g, 4.611 mmol),and NaI (0.693 g, 4.623 mmol) were dissolved in anhydrous DMF (30 mL)under inert gas and cooled in an ice bath. NaH (60% dispersion inmineral oil, 0.288 g, 7.20 mmol) was carefully added to the reactionmixture by briefly exposing the system to air. The reaction mixture wasstirred for 3 hours at room temperature and quenched with a 50% dilutionof sat. NaHCO₃. The mixture was extracted with three portions of etherwhich were combined, washed with brine, dried with Na₂SO₄, andconcentrated. The crude material was purified by column chromatographyusing a gradient of 100% hexane to 25% EtOAc/hexane to give the desiredproduct 11b as a yellow solid (1.302 g, 2.384 mmol, 51.8%). TLC R_(f)(25% EtOAc/Hexane)=0.45. Mp 51-54° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm7.99 (2H, d, J=8.2 Hz), 7.64 (3H, m), 7.47 (2H, d, J=8.5 Hz), 7.15 (2H,bd, J=8.1 Hz), 6.39 (1H, d, J=16.0 Hz), 4.95 (2H, s), 4.25 (2H, q, J=7.1Hz), 2.21 (3H, s), 1.47 (9H, s), 1.32 (3H, t, J=7.1 Hz). ¹³C NMR (CDCl₃,150 MHz): δ ppm 166.99, 164.25, 154.12, 151.53, 143.62, 143.41, 136.79,132.80, 131.47 (q, ²J_(FC)=32 Hz), 129.59, 128.76, 127.43, 126.59,126.00 (m), 124.02 (q, ¹J_(FC)=270 Hz), 118.69, 81.75, 60.70, 45.86,28.41, 15.15, 14.43. Anal. Calcd for C₂₈H₂₉F₃N₂O₄S: C, 61.53; H, 5.35;N, 5.13. Found: C, 61.63; H, 5.53; N, 5.27.

Ethyl4-[N-[5-Methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamate(12b)

BOC protected amine 11b (1.140 g, 2.085 mmol) was dissolved in anhydrousDCM (15 mL) and cooled in an ice bath. Trifluoroacetic acid (3 mL) wasadded slowly and the mixture was stirred at room temperature for 2hours. The reaction mixture was then washed with a chilled saturatedNaHCO₃ solution, water, brine, and dried with Na₂SO₄. After filtrationand evaporation of the solvent, the crude product was purified withcolumn chromatography using a gradient of 10% EtOAc/hexane to 25%EtOAc/hexane. The purified product 12b was collected as an ivory solid(0.793 g, 1.776 mmol, 85.2%). TLC R_(f) (25% EtOAc/Hexane)=0.20. Mp120-122° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.98 (2H, d, J=8.1 Hz), 7.65(2H, d, J=8.2 Hz), 7.60 (1H, d, J=15.9 Hz), 7.39 (2H, d, J=8.6 Hz), 6.65(2H, d, J=8.6 Hz), 6.24 (1H, d, J=15.9 Hz), 4.52 (2H, s), 4.24 (2H, q,J=7.1 Hz), 2.51 (3H, s), 1.32 (3H, t, J=7.1 Hz). ¹³C NMR (CDCl₃, 150MHz): δ ppm 167.79, 163.90, 150.59, 148.79, 144.77, 136.67, 131.61 (q,²J_(FC)=32.5 Hz), 131.22, 130.05, 126.60, 126.05 (m), 125.05, 124.02 (q,¹J_(FC)=270 Hz), 114.08, 113.18, 60.36, 40.37, 15.47, 14.53. Anal. Calcdfor C₂₃H₂₁F₃N₂O₂S: C, 61.87; H, 4.74; N, 6.27. Found: C, 61.73; H, 4.77;N, 6.37.

4-[N-[5-Methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamicAcid (BK-4-03)

Methyl ester 12b (0.595 g, 1.333 mmol) was dissolved in a mixture of THF(10 mL) and 95% ethanol (10 mL). A 3N NaOH solution (2 mL) was added andthe reaction mixture was stirred for 24 hours. After reaction wasdetermined complete by TLC, 1N HCl was added to pH=3. Organic solventswere removed under reduced pressure and the residue was extracted withEtOAc. The organic extract was washed with brine, dried with Na₂SO₄, andconcentrated. The crude material was purified by column chromatographyusing a 25% EtOAc/Hexane to 30% EtOAc/Hexane gradient supplemented withdropwise amounts of acetic acid to give the desired product BK-4-03 as ayellow solid (0.153 g, 0.365 mmol, 27.4%). TLC R_(f) (50%EtOAc/Hexane)=0.35. Mp 224-226° C. ¹H NMR (Acetone-d6, 600 MHz): δ ppm10.42 (1H, bs), 8.12 (2H, d, J=8.2 Hz), 7.79 (2H, d, J=8.3 Hz), 7.56(1H, d, J=15.8), 7.48 (2H, d, J=8.6 Hz), 6.77 (2H, d, J=8.7 Hz), 6.24(2H, m), 4.65 (2H, s), 2.50 (3H, s). ¹³C NMR (Acetone-d6, 150 MHz): δppm 168.35, 163.07, 151.11, 150.95, 146.07, 138.17, 134.09, 131.35 (q,²J_(FC)=31.8 Hz), 130.76, 127.22, 126.85 (m), 125.15 (q, ¹J_(FC)=270Hz), 124.46, 113.61, 113.58, 40.17, 15.40. ¹⁹F NMR (Acetone-d6, 376MHz): δ ppm −63.64 (s, 3F). Anal. Calcd for C₂₁H₁₇F₃N₂O₂S (with 0.4 molH₂O per target): C, 59.26; H, 4.22; N, 6.58. Found: C, 59.41; H, 4.58;N, 6.36.

Ethyl4-(N-tert-Butoxycarbonyl)-[N-[5-methylene-4-methyl-2-[3-(trifluoromethyl)phenyl]thiazole]]aminocinnamate (11c)

Ethyl ester 10 (1.313 g, 4.507 mmol), thiazole 4c (1.315 g, 4.509 mmol)and NaI (0.680 g, 4.538 mmol) were dissolved in anhydrous DMF (34 mL)and cooled to 0° C. in an ice bath. The mixture was briefly exposed toair and NaH (60% dispersion in mineral oil, 0.277 g, 6.925 mmol) wasadded. The reaction mixture was warmed to room temperature and stirredfor 2 hours. The solution was quenched with water and diluted with a 1:1mixture of aqueous NaHCO₃ and ether. The two phase mixture was separatedand the isolated aqueous phase was extracted twice with ether. Theorganic phase extracts were combined, washed with brine, dried overNa₂SO₄, filtered, and concentrated. The crude sample was purified withsilica gel column chromatography using a 100% hexane to 15% EtOAc/hexanegradient to give 1c as a viscous yellow oil (1.621 g, 2.966 mmol,65.8%). TLC R_(f) (25% EtOAc/hexane)=0.35. ¹H NMR (CDCl₃, 600 MHz): δppm 8.18 (1H, s), 8.05 (1H, d, J=7.8 Hz), 7.65 (2H, m), 7.55 (1H, t,J=7.8 Hz), 7.49 (2H, d, J=8.5 Hz), 7.17 (2H, d, J=8.1 Hz), 6.41 (1H, d,J=16.0 Hz), 4.98 (2H, s), 4.28 (2H, q, J=7.1 Hz), 2.23 (3H, s), 1.49(9H, s), 1.35 (3H, t, J=7.1 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.00,164.36, 154.15, 151.38, 143.63, 143.41, 134.40, 132.82, 131.56 (q,²J_(FC)=32 Hz), 129.62, 129.56, 128.77, 126.44 (m), 123.93 (q,¹J_(FC)=271 Hz), 123.15 (m), 118.70, 81.75, 60.70, 45.85, 28.43, 15.13,14.45. Anal. Calcd for C₂₈H₂₉F₃N₂O₄S: C, 61.53; H, 5.35; N, 5.13. Found:C, 61.39; H, 5.48; N, 5.01.

Ethyl4-[N-[5-Methylene-4-methyl-2-[3-(trifluoromethyl)phenyl]thiazole]]aminocinnamate(12c)

BOC protected amine 1c (1.30 g, 2.378 mmol) was dissolved in anhydrousDCM (15 mL) and was cooled in an ice bath at 0° C. Trifluoroacetic acid(3 mL) was added and the mixture was stirred for 2 hours. The mixturewas then washed with cold saturated NaHCO₃, brine, dried over Na₂SO₄,filtered, and concentrated. The crude sample was purified using silicagel column chromatography and a 10% to 25% EtOAc/hexane gradient to give12c as a light yellow solid (0.811 g, 1.817 mmol, 76.4%). TLC R_(f) (25%EtOAc/Hexane)=0.23. Mp 133-135° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 8.14(1H, s), 8.02 (1H, d, J=7.9 Hz), 7.63 (1H, d, J=7.8 Hz), 7.60 (1H, d,J=15.9 Hz), 7.52 (1H, m), 7.39 (2H, d, J=8.6 Hz), 6.64 (2H, d, J=8.6Hz), 6.24 (2H, d, J=15.9 Hz), 4.51 (2H, s), 4.23 (2H, q, J=7.1 Hz), 2.51(3H, s), 1.32 (3H, t, J=7.1 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.80,163.89, 150.44, 148.92, 134.40, 131.57 (q, ²J_(FC)=32 Hz), 130.94,130.05, 129.57, 129.52, 126.42 (m), 124.90, 123.92 (q, ¹J_(FC)=271 Hz),123.10 (m), 113.97, 113.08, 60.33, 40.29, 15.46, 14.51. Anal. Calcd forC₂₃H₂F₃N₂O₂S: C, 61.87; H, 4.74; N, 6.27. Found: C, 61.87; H, 4.79; N,6.26.

4-[N-[5-methylene-4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]thiazole]]aminocinnamicAcid (BK-4-30)

Ethyl ester 12c (0.629 g, 1.409 mmol) was dissolved in 95% ethanol (10mL) and THF (10 mL). The mixture was cooled in an ice bath at 0° C. and3N NaOH (2 mL) was added. The mixture was stirred at room temperatureovernight and acidified with 1N HCl to a pH near 3. Organic solventswere removed under reduced pressure and the residue was taken up intoEtOAc. The mixture was washed with a chilled saturated NaHCO₃ solution,brine, dried over Na₂SO₄, filtered, and concentrated. The crude samplewas purified using silica gel column chromatography with a 25%EtOAc/hexane mobile phase that was supplemented with dropwise amounts ofglacial acetic acid. A yellow-white solid was collected (0.474 g) andrecrystallized using 95% ethanol to give the desired product BK-4-30 asa light yellow solid (0.122 g, 0.292 mmol, 20.7%). TLC R_(f)(50%EtOAc/Hexane)=0.33. Mp 171-173° C. ¹H NMR (Acetone-d6,600 MHz): δ ppm8.22 (1H, s), 8.13 (1H, d, J=7.9 Hz), 7.77 (1H, d, J=7.8 Hz), 7.70 (1H,t, J=7.8 Hz), 7.56 (1H, d, J=15.8 Hz), 7.47 (2H, d, J=8.6 Hz), 6.76 (2H,d, J=8.7 Hz), 6.24 (2H, d, J=15.8 Hz), 4.64 (2H, s), 2.50 (3H, s). ¹³CNMR (Acetone-d6, 150 MHz): δ ppm 168.41, 163.08, 150.95, 150.93, 146.09,135.61, 133.69, 131.67 (q, ²J_(FC)=32 Hz), 131.05, 130.76, 130.47,126.88 (m), 125.02 (q, ¹J_(FC)=270 Hz), 124.45, 113.61, 113.58, 40.17,15.38. ¹⁹F NMR (Acetone-d6, 150 MHz): δ ppm −63.76 (3F, s). Anal. Calcdfor C₂₁H₁₇F₃N₂O₂S: C, 60.28; H, 4.10; N, 6.69. Found: C, 60.16; H, 4.15;N, 6.65.

Ethyl4-(N-tert-butoxycarbonyl)-[N-[5-methylene-4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]thiazole]]cinnamate(11d)

Ethyl ester 10 (1.274 g, 4.373 mmol) and thiazole 4d (1.314 g, 4.250mmol) were dissolved in anhydrous DMF (35 mL) and cooled to 0° C. NaI(0.677 g, 4.520 mmol) was added and the mixture was warmed to roomtemperature and stirred for 1.5 hours. The solution was then quenchedwith water and extracted with ether/NaHCO₃ solution three times. Theether extracts were combined and washed with brine and dried withNa₂SO₄. The crude yellow-orange oil was concentrated and purified usingcolumn chromatography with a 100% hexane to 15% EtOAc/hexane gradientyielding the desired product 11d as a yellow solid (1.075 g, 1.90 mmol,53%). TLC R_(f) (25% EtOAc/Hexane)=0.43. Mp 64-66° C. ¹H NMR (CDCl₃, 600MHz): δ ppm 7.73 (2H, m), 7.64 (2H, m), 7.49 (2H, d, J=8.4 Hz), 7.16(2H, d, J=8.2 Hz), 6.41 (1H, d, J=15.9 Hz), 4.97 (2H, s), 4.27 (2H, q,J=7.14 Hz), 2.22 (3H, s), 1.47 (9H, s), 1.34 (3H, t, J=7.14 Hz). ¹³C NMR(CDCl₃, 150 MHz): δ ppm 166.85, 162.60, 159.52 (d, ¹J_(FC)=254 Hz),153.99, 151.66, 143.45, 143.22, 139.10 (d, ¹J_(FC)=8.4 Hz), 132.75,130.29, 128.67, 127.79, 127.78 (d, ¹J_(FC)=3.3 Hz), 127.28, 122.42 (q,¹J_(FC)=269 Hz) 121.67, 119.00 (dq, ²J_(FC)=33 Hz, ²J_(FC)=13 Hz)118.65, 114.32 (d, ¹J_(FC)=22 Hz), 81.72, 60.60, 28.30, 15.02, 14.33.Anal. Calcd for C₂₈H₂₈F₄N₂O₄S: C, 59.57; H, 5.00; N, 4.96. Found: C,59.30; H, 5.13; N, 4.95.

Ethyl4-[N-[5-Methylene-4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]thiazole]]aminocinnamate (12d)

BOC protected amine 11d (0.684 g, 1.473 mmol) was dissolved is DCManhydrous (15 mL) and the solution was cooled to 0° C. beforetrifluoroacetic acid (5 mL) was added. After 1.5 hours, the reactionmixture was concentrated under reduced pressure. The solid yellow crudeproduct was purified using column chromatography with a 100% hexane to35% EtOAc/hexane gradient yielding the desired product 12d as a yellowsolid (0.296 g, 0.637 mmol, 44%). TLC R_(f) (25% EtOAc/Hexane)=0.20. Mp138-140° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.77 (1H, d, J=11.2 Hz), 7.72(1H, d, J=8.3 Hz), 7.63 (2H, m), 7.42 (2H, d, J=8.6 Hz), 6.68 (2H, d,J=8.6 Hz), 6.28 (1H, d, J=15.9 Hz), 4.51 (2H, s), 4.26 (2H, m), 2.52(3H, s), 1.34 (3H, t, J=7.14 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm169.86, 162.15, 160.01 (d, ¹J_(FC)=255 Hz), 150.74, 148.53, 144.60,139.8 (d, ¹J_(FC)=8.3 Hz), 132.02, 129.93, 129.21, 127.80 (d,¹J_(FC)=4.2 Hz), 125.02, 122.39 (q, ¹J_(FC)=270 Hz), 121.62, 118.97 (dq,²J_(FC)=33 Hz, ²J_(FC)=13 Hz), 117.96, 114.25 (d, ¹J_(FC)=22 Hz), 60.25,40.28, 15.36, 14.39. Anal. Calcd for C₂₃H₂F₄N₂O₂S: C, 59.48; H, 4.34; N,6.03. Found: C, 59.48; H, 4.24; N, 6.00.

4-[N-[5-Methylene-4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]thiazole]]aminocinnamicAcid (JF-4-94)

Ethyl ester 12d (97.5 mg, 0.210 mmol) was suspended in 95% EtOH (10 mL)and achieved complete solubility after addition of 3N NaOH (1.0 mL).Reaction mixture was stirred at r.t overnight and was then concentrated.The resulting residue was suspended in EtOAc and washed with acidifiedwater (HCl, pH=3), water, brine, and dried with Na₂SO₄. The crudematerial was purified by column chromatography using a 25% EtOAc/Hexaneto 40% EtOAc/Hexane gradient supplemented with dropwise amounts ofacetic acid to give the desired product as a yellow solid (90.6 mg). Theproduct was recrystallized using 95% ethanol to give JF-4-94 as acream-colored crystalline solid (24.0 mg, 0.054 mmol, 26.2%). TLC R_(f)(50% EtOAc/Hexane)=0.30. Mp 213-214° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm7.89 (2H, d, J=9.8 Hz), 7.82 (1H, t, J=7.71 Hz), 7.57 (1H, d, J=15.9Hz), 7.48 (2H, d, J=8.6 Hz), 6.76 (2H, d, J=8.6 Hz), 6.25 (1H, d, J=15.9Hz), 4.65 (2H, s), 2.50 (3H, s), 1.96 (3H, s). ¹³C NMR (CDCl₃, 150 MHz):δ ppm 167.45, 160.68, 158.99, 150.39, 149.94, 145.19, 139.92 (d,⁴J_(FC)=8.5 Hz), 134.44, 133.13, 129.88, 128.13 (d, ³J_(FC)=4.1 Hz),123.63, 122.8 (q, ¹J_(FC)=270 Hz), 121.90, 117.8 (dq, ²J_(FC)=33 Hz,²J_(FC)=13 Hz), 113.59 (d, ¹J_(FC)=22 Hz), 112.72, 39.25, 14.50. Anal.Calcd for C₂₁H₁₆F₄N₂O₂S: C, 57.79; H, 3.70; N, 6.42. Found: C, 57.74; H,3.72; N, 6.28.

4-[N-(tert-Butoxycarbonyl)-N-[5-methylene-4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]thiazole]]aminocinnamicAcid. (JF-4-98)

Ethyl ester 11d (206 mg, 0.365 mmol) was dissolved in 95% EtOH (10 mL)and 3N NaOH (1.0 mL) was added. The reaction mixture was stirred at roomtemperature overnight and was concentrated under reduced pressure. Theresulting residue was suspended in EtOAc and washed with acidified water(HCl, pH=3), neutral water, brine and dried with Na₂SO₄. Crude productwas purified by column chromatography using a 20% EtOAc/hexane to 35%EtOAc/hexane gradient supplemented with dropwise amounts of acetic acidto give the desired product as a white solid. The solid wasrecrystallized with 95% EtOH giving JF-4-98 as a crystalline white solidproduct (107.5 mg, 0.2004 mmol, 55%). TLC R_(f) (50% EtOAc/Hexane)=0.46.Mp 212-214° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.92 (2H, m), 7.84 (1H, t,J=7.8 Hz), 7.68 (2H, d, J=8.4 Hz), 7.64 (1H, d, J=15.9 Hz), 7.33 (2H, d,J=8.4 Hz), 6.50 (1H, d, J=15.9 Hz), 5.12 (2H, s), 2.22 (3H, s), 1.46(9H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 166.73, 161.61, 159.83 (d,¹J_(FC)=253 Hz), 153.62, 151.81, 143.61, 143.52, 139.79 (d, ³J_(FC)=8.6Hz), 132.53, 131.26, 128.64, 128.17 (d, ³J_(FC)=4.1 Hz), 127.39, 122.74(q, ¹J_(FC)=270 Hz), 122.08, 118.48, 117.89 (dq, ²J_(FC)=33 Hz,²J_(FC)=13 Hz), 113.76 (d, ¹J_(FC)=23 Hz), 80.78, 45.23, 27.49, 14.26.Anal. Calcd for C₂₆H₂₄F₄N₂O₄S: Theory: C, 58.20; H, 4.51; N, 5.22.Found: C, 57.93; H, 4.63; N, 5.08.

Ethyl 4-[N-(tert-butoxycarbonyl)methyl]aminocinnamate (14)

Ethyl 4-N-tert-butoxycarbonyl)aminocinnamate 10 (0.935 g, 3.211 mmol)was dissolved in anhydrous DMF (17 mL) and cooled in an ice bath. NaH(60% dispersion in oil, 0.198 g, 4.95 mmol) was added and the mixturewas stirred for 60 minutes followed by addition of iodomethane (0.60 mL,9.63 mmol). The reaction mixture was stirred overnight at roomtemperature and quenched with a 50% aqueous solution of NaHCO₃ andextracted twice with ether. The ether extracts were combined and washedwith brine, dried with Na₂SO₄, and concentrated. The crude material waspurified by column chromatography using a 10% EtOAc/hexane mobile phasegiving the product 14 as an off-white solid (0.897 g, 2.937 mmol,91.5%). TLC R_(f) (25% EtOAc/Hexane)=0.53. Mp 44-45° C. ¹H NMR (CDCl₃,600 MHz): δ ppm 7.65 (1H, d, J=16.0 Hz), 7.47 (2H, d, J=8.5 Hz), 7.27(2H, d, J=8.5 Hz), 6.38 (1H, d, J=16.0 Hz), 4.25 (2H, q, J=7.1 Hz), 3.27(3H, s), 1.46 (9H, s), 1.33 (3H, t, J=7.1 Hz). ¹³C NMR (CDCl₃, 150 MHz):δ ppm 167.19, 154.48, 145.60, 143.97, 131.21, 128.40, 125.34, 117.84,80.97, 60.61, 37.10, 28.42, 14.46. Anal. Calcd for C₁₆H₂₁NO₄: C, 66.86;H, 7.59; N, 4.59. Found: C, 66.60; H, 7.52; N, 4.45.

Ethyl 4-(N-Methyl)aminocinnamate (15)

Ethyl 4-[N-(tert-butoxycarbonyl)methyl]aminocinnamate 14 (0.775 g, 2.538mmol) was dissolved in anhydrous DCM (20 mL) and cooled in an ice bath.Trifluoroacetic acid (5 mL) was slowly added and the mixture was allowedto warm to room temperature. The mixture was stirred for 90 minutes andthe solvent was removed under reduced pressure. The residue was taken upinto EtOAc and washed with chilled saturated NaHCO₃, brine, dried withNa₂SO₄, filtered, and concentrated. The crude material was purified bycolumn chromatography using 10% EtOAc/Hexane to give the product 15 as ayellow solid (0.474 g, 2.307 mmol, 90.9%). TLC R_(f)(25%EtOAc/Hexane)=0.37. Mp 49-50° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.61(1H, d, J=15.8 Hz), 7.37 (2H, d, J=8.5 Hz), 6.56 (2H, d, J=8.6 Hz), 6.21(1H, d, J=15.8 Hz), 4.23 (2H, q, J=7.1 Hz), 4.08 (1H, bs), 2.87 (3H, s),1.32 (3H, t, J=7.1 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 168.00, 151.17,145.26, 130.01, 123.47, 112.86, 112.20, 60.21, 30.41, 14.53. Anal. Calcdfor C₁₂H₁₅NO₂: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.03; H, 7.25; N,6.71.

Ethyl4-[N-Methyl-N-[5-methylene-4-methyl-2-phenylthiazole]]aminocinnamate(16a)

Ethyl 4-(N-Methyl)aminocinnamate 15 (0.200 g, 0.974 mmol), thiazole 4a(0.238 g, 1.063 mmol), and NaI (0.180 g, 1.200 mmol) were dissolved inanhydrous DMF (15 mL) and cooled in an ice bath. NaH (60% dispersion inoil, 0.080 g, 2.000 mmol) was added and the reaction mixture was stirredat room temperature for 3.5 hours. The reaction mixture was diluted withether and washed with a 10% aqueous NaHCO₃ solution. The organic phasewas collected and the aqueous phase was extracted with ether 3 times.The combined organic extracts were washed with brine, dried with Na₂SO₄,filtered, and concentrated. Purification by silica gel plug wasunsuccessful and the yellow oil crude product 16a (0.346 g, 0.881 mmol,90.5%) was moved to the next step. TLC R_(f) (25% EtOAc/Hexane)=0.35.

4-[N-Methyl-N-[5-methylene-4-methyl-2-phenylthiazole]]aminocinnamic Acid(BK-4-43)

Ethyl ester 16a (0.205 g, 0.522 mmol) was dissolved in 95% ethanol (5mL) and THF (5 mL). The solution was cooled in an ice bath and 3N NaOH(1 mL) was added and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated and the residue wastaken up into EtOAc and acidified water (HCl, pH=3). The organic phasewas collected and washed with brine, dried with Na₂SO₄, filtered, andconcentrated. The crude product was purified by column chromatographyusing a 25% EtOAc/Hexane mobile phase spiked with dropwise amounts ofacetic acid. The collected product was recrystallized using a mixture of95% ethanol and EtOAc to give the product BK-4-43 as a light yellowsolid (0.061 g, 0.167 mmol, 32.0%). TLC R_(f) (50% EtOAc/Hexane)=0.36.Mp 196-197° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.88 (2H, m), 7.58 (1H, d,J=15.8 Hz), 7.54 (2H, d, J=8.8 Hz), 7.42 (3H, m), 6.90 (2H, d, J=8.9Hz), 6.27 (1H, d, J=15.9 Hz), 4.85 (2H, s), 3.10 (3H, s), 2.48 (3H, s).¹³C NMR (CDCl₃, 150 MHz): δ ppm 168.38, 165.16, 151.48, 150.94, 145.88,134.74, 130.74, 130.70, 129.90, 126.81, 124.24, 114.07, 113.71, 49.09,38.46, 15.57. Anal. Calcd for C₂₁H₂₀N₂O₂S: C, 69.12; H, 5.53; N, 7.69.Found: C, 69.03; H, 5.69; N, 7.76.

Ethyl4-[N-Methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamate(16b)

Ethyl 4-(N-Methyl)aminocinnamate 15 (0.430 g, 2.094 mmol), thiazole 4b(0.661 g, 2.265 mmol), and NaI (0.336 g, 2.241 mmol) were dissolved inanhydrous DMF (15 mL) and cooled in an ice bath. NaH (60% dispersion inoil, 0.132 g, 3.300 mmol) was added and the reaction mixture was stirredat room temperature for 2 hours. The reaction mixture was quenched withwater, diluted with ether, and washed with a 10% aqueous NaHCO₃solution. The organic phase was collected and the aqueous phase wasextracted with ether three times. The combined organic extracts werewashed with brine, dried with Na₂SO₄, filtered, and concentrated.Separation of the starting material and desired product by silica gelcolumn chromatography was unsuccessful and the yellow-orange oil 16b(0.721 g, 1.565 mmol, 74.7%) was moved to the next step. TLC R_(f)(25%EtOAc/Hexane)=0.36.

4-[N-Methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamicAcid (BK-4-15)

Ethyl ester 16b (0.555 g, 1.205 mmol) was dissolved in 95% ethanol (5mL) and THF (5 mL). The solution was cooled in an ice bath and 3N NaOH(1 mL) was added and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated and the residue wastaken up into EtOAc and acidified water (HCl, pH=3). The organic phasewas collected and washed with brine, dried with Na₂SO₄, filtered, andconcentrated. The crude product was purified by column chromatographyusing a 25% EtOAc/Hexane mobile phase spiked with dropwise amounts ofacetic acid. The collected product was recrystallized using EtOAc togive the product BK-4-15 as a yellow solid (0.338 g, 0.782 mmol, 64.9%).TLC R_(f) (50% EtOAc/Hexane)=0.40. Mp 210-212° C. ¹H NMR (CDCl₃, 600MHz): δ ppm 8.10 (2H, d, J=8.1 Hz), 7.79 (2H, d, J=8.3 Hz), 7.59 (1H, d,J=15.9 Hz), 7.56 (2H, d, J=8.9 Hz), 6.91 (2H, d, 8.9 Hz), 6.29 (1H, d,J=15.9 Hz), 4.88 (2H, s), 3.12 (3H, s), 2.52 (3H, s). ¹³C NMR (CDCl₃,150 MHz): δ ppm 186.31, 163.13, 151.47, 151.33, 145.79, 138.11, 132.60,131.45 (q, ²J_(FC)=32.6 Hz), 130.73, 127.32, 126.90 (m), 124.34, 114.16,113.70, 49.15, 38.53. Anal. Calcd for C₂₂H₁₉F₃N₂O₂S: C, 61.10; H, 4.43;N, 6.48. Found: C, 61.11; H, 4.41; N, 6.49.

Ethyl4-[N-Methyl-N-[5-methylene-4-methyl-2-[3-(trifluoromethyl)phenyl]thiazole]]aminocinnamate(16c)

Ethyl 4-(N-Methyl)aminocinnamate 15 (0.247 g, 1.203 mmol), thiazole 4c(0.407 g, 1.395 mmol), and NaI (0.213 g, 1.421 mmol) were dissolved inanhydrous DMF (15 mL) and cooled in an ice bath. NaH (60% dispersion inoil, 0.085 g, 2.125 mmol) was added and the reaction mixture was stirredat room temperature for 3.5 hours. The reaction mixture was quenchedwith water, diluted with ether, and washed with a 10% aqueous NaHCO₃solution. The organic phase was collected and the aqueous phase wasextracted with ether/sat. NaHCO₃ three times. The combined organicextracts were washed with brine, dried with Na₂SO₄, filtered, andconcentrated. Separation of the starting material and desired product bysilica gel column chromatography was unsuccessful and the yellow solid16c (0.250 g, 0.543 mmol, 45.1%) was moved to the next step. TLC R_(f)(25% EtOAc/Hexane)=0.45.

4-[N-Methyl-N-[5-methylene-4-methyl-2-[3-(trifluoromethyl)phenyl]thiazole]]aminocinnamicAcid (BK-4-38)

Ethyl ester 16c (0.240 g, 0.521 mmol) was dissolved in 95% ethanol (5mL) and THF (5 mL). The solution was cooled in an ice bath and 3N NaOH(1 mL) was added and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated and the residue wastaken up into EtOAc and acidified water (HCl, pH=3). The organic phasewas collected and washed with brine, dried with Na₂SO₄, filtered, andconcentrated. The crude product was purified by column chromatographyusing a 25% EtOAc/Hexane mobile phase spiked with dropwise amounts ofacetic acid. The collected product was recrystallized using EtOH to givethe product BK-4-38 as a yellow solid (0.098 g, 0.226 mmol, 43.5%). TLCR_(f) (50% EtOAc/Hexane)=0.35. Mp 217° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm8.21 (1H, s), 8.12 (1H, d, J=7.8 Hz), 7.76 (1H, d, J=7.8 Hz), 7.70 (1H,t, J=7.8 Hz), 7.59 (1H, d, J=15.9 Hz), 7.56 (2H, d, J=8.6 Hz), 6.90 (2H,d, J=8.8 Hz), 6.29 (1H, d, J=15.8 Hz), 4.88 (2H, s), 3.12 (3H, s), 2.51(3H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 168.33, 163.13, 151.33, 151.29,145.83, 135.55, 132.24, 131.70 (q, ²J_(FC)=32.5 Hz), 131.10, 130.73,130.56, 126.98 (q, ³J_(FC)=3.7 Hz), 126.85 (q, ¹J_(FC)=270 Hz), 124.30,122.92 (q, ³J_(FC)=3.6 Hz), 114.09, 113.66, 49.12, 38.51, 15.51. Anal.Calcd for C₂₂H₁₉F₃N₂O₂S: C, 61.10; H, 4.43; N, 6.48. Found: C, 60.92; H,4.45; N, 6.45.

Ethyl4-[N-Methyl-N-[5-methylene-4-methyl-2-[3-fluoro-4-(trifluromethyl)phenyl]thiazole]]aminocinnamate (16d)

To a stirred solution of ethyl ester 15 (0.2885 g, 1.405 mmol), thiazole4d (0.4754 g, 1.535 mmol), and NaI (0.2384 g, 1.590 mmol) in anhydrousDMF (12 ml) was added NaH (0.0697, 2.904 mmol) slowly while at 0° C. Themixture was stirred at room temperature for 3 hours and turned from ayellow to a dark orange color. Then the reaction mixture was quenchedwith water and extracted with diethyl ether twice. The ether extractswere combined and washed with brine and dried with Na₂SO₄. The residuewas concentrated then purified by column chromatography on silica gelwith 5 to 20% gradient of ethyl acetate/hexane to give the desiredproduct 16d as an orange solid (0.192 g, 0.401 mmol, 28.5%). TLC R_(f)(25% EtOAc/Hexane)=0.43. Mp 142° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.73(1H, m), 7.67 (1H, m), 7.63 (2H, m), 7.45 (2H, d, J=8.8 Hz), 6.76 (2H,d, J=8.8 Hz), 6.26 (1H, d, J=16 Hz), 4.68 (2H, s), 4.26 (2H, q, J=7.14Hz), 3.05 (3H, s), 2.50 (3H, s), 1.33 (3H, t, J=7.14 Hz). ¹³C NMR(CDCl₃, 150 MHz): δ ppm 167.81, 161.97, 160.97 (d, ¹J_(FC)=254 Hz),150.57, 150.09, 144.69, 139.29 (d, ⁴J_(FC)=8.6 Hz), 131.88, 129.99,127.85, 124.07, 123.42 (q, ¹J_(FC)=270 Hz), 121.70 (d, ³J_(FC)=3.5),119.16 (dq, ²J_(FC)=14 Hz, ²J_(FC)=33 Hz), 114.40 (d, ²J_(FC)=23 Hz),113.97, 112.85, 60.33, 49.15, 38.42, 15.57, 14.53. Anal. Calcd forC₂₄H₂₂F₄N₂O₂S (with 0.3 water mol per target): C, 59.57; H, 4.71; N,5.79. Found: C, 59.19; H, 4.55; N, 5.74.

4-[N-Methyl-N-[5-methylene-4-methyl-2-[3-fluoro-4-(trifluormethyl)phenyl]thiazole]]aminocinnamicAcid (JM-4-68)

To a stirred solution of ethyl ester 16d (0.157 g, 0.328 mmol) in THF (5ml) and 95% ethanol (5 ml) was added 3 N NaOH (1 ml) slowly. The mixturewas stirred at room temperature overnight and concentrated. The residuewas taken up in EtOAc then washed with acidified water (HCl, pH=3),brine and dried with Na₂SO₄. The residue was concentrated then purifiedby column chromatography on silica gel with a gradient of 25% to 50%EtOAc/Hexanes including drop-wise amount of acetic acid to give theproduct JM-4-68 as an orange solid (0.045 g, 0.010 mmol, 31%). TLC R_(f)(50% EtOAc/Hexanes)=0.36. Mp 214° C. ¹H NMR (Acetone-d₆, 600 MHz): δ ppm7.86 (2H, m), 7.81 (1H, m), 7.60 (1H, d, J=16 Hz), 7.56 (2H, d, J=8.9Hz), 6.91 (2H, d, J=8.9 Hz), 6.29 (1H, d, J=16 Hz), 4.89 (2H, s), 3.12(3H, s), 2.52 (3H, s). ¹³C NMR (Acetone-d₆, 150 MHz): δ ppm 168.30,161.56, 159.86 (d, ¹J_(FC)=255 Hz), 151.61, 151.21, 145.74, 140.72 (d,⁴J_(FC)=9 Hz), 133.73, 130.69, 129.04 (m), 124.52 (q, ¹J_(FC)=270 Hz),124.33, 122.87 (d, ³J_(FC)=3.3 Hz), 118.85 (dq, ²J_(FC)=33 Hz,²J_(FC)=12 Hz), 114.60 (d, ²J_(FC)=23 Hz), 114.14, 113.63, 49.16, 38.54,15.47. Anal. Calcd for C₂₂H₁₈F₄N₂O₂S: C, 58.66; H, 4.03; N, 6.22. Found:C, 58.43; H, 4.09; N, 6.21.

Ethyl 4-[N-Ethyl-N-(tert-butoxycarbonyl)]aminocinnamate (17a)

To a stirred solution of N-ethyl-cinnamate 10 (1.459 g, 5.01 mmol) inanhydrous DMF (20 mL) under inert gas at 0° C. was added NaH (60%dispersion in mineral oil, 0.317 g, 13.208 mmol). Mixture stirred for 1hour and iodoethane (1.2 mL, 14.9 mmol) was then added and mixturecontinued to stir at room temperature overnight. The mixture was thendiluted with 50% sodium bicarbonate solution and extracted with etherthree times. The ether extracts were combined and washed with brine,dried with Na₂SO₄, filtered and concentrated. The residue wasconcentrated then purified by column chromatography on silica gel with agradient of 10% to 15% ethyl acetate/hexane to give the desired product17a as a yellow solid (1.253 g, 3.923 mmol, 78.3%). TLC R_(f) (25%EtOAc/Hexane)=0.56. Mp 58-60° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.67(1H, d, J=16.0 Hz), 7.49 (2H, d, J=8.4 Hz), 7.23 (2H, d, J=8.4 Hz), 6.40(1H, d, J=16.0 Hz), 4.28 (2H, q, J=7.1 Hz), 3.71 (2H, q, J=7.0 Hz), 1.44(9H, s), 1.35 (3H, t, J=7.1 Hz), 1.17 (3H, t, J=7.0 Hz). ¹³C NMR (CDCl₃,150 MHz): δ ppm 167.19, 154.30, 144.44, 143.99, 131.82, 128.54, 126.93,118.04, 80.62, 60.65, 44.93, 28.46, 14.47, 14.10. Anal. Calcd forC₁₈H₂₅NO₄: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.62; H, 7.90; N,4.42.

Ethyl 4-(N-Ethyl)-aminocinnamate (18a)

To a stirred solution of ethyl ester 17a (1.143 g, 3.579 mmol) inanhydrous DCM (25 mL) under inert gas at 0° C. was slowly addedtrifluoroacetic acid (6 mL). The mixture was allowed to warm to roomtemperature and stirred for 2 hours. The reaction mixture was thenconcentrated and the residue was taken up into EtOAc and washed withcold saturated NaHCO₃, brine, dried with NaSO₄, and filtered. Thefiltrated was concentrated and the resulting residue was purified bycolumn chromatography using a 5% to 10% EtOAc/hexane mobile phase togive the desired product 18a as a light yellow solid (0.741 g, 3.380mmol, 94.4%). TLC R_(f) (25% EtOAc/hexane)=0.43. Mp 65-67° C. ¹H NMR(CDCl₃, 600 MHz): δ ppm 7.61 (1H, d, J=16.0 Hz), 7.39 (2H, d, J=8.5 Hz),6.61 (2H, d, J=8.5), 6.22 (1H, d, J=16.0 Hz), 4.25 (2H, q, J=7.1 Hz),3.22 (2H, q, J=7.2 Hz), 1.33 (3H, t, J=7.1 Hz), 1.28 (3H, t, J=7.2 Hz).¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.95, 149.63, 145.12, 130.05, 124.15,113.24, 113.09, 60.26, 38.70, 14.66, 14.55. Anal. Calcd for C₁₃H₁₇NO₂:C, 71.21; H, 7.81; N, 6.39. Found: C, 71.01; H, 7.75; N, 6.33.

Ethyl4-[N-Ethyl-N-[5-methylene-4-methyl-2-[4-(trifluormethyl)phenyl]thiazole]]aminocinnamate(19a)

To a stirred solution of ethyl ester 18a (0.226 g, 1.031 mmol), thiazole4b (0.3032 g, 1.039 mmol), and NaI (0.184 g, 1.228 mmol) in anhydrousDMF (15 mL) and was added NaH (60% dispersion in mineral oil, 0.0612 g,2.550 mmol) slowly while at 0° C. The mixture then stirred at rt for 3.5hours. The mixture was quenched with 10% NaHCO₃ solution and extractedwith diethyl ether three times. The ether extracts were combined andwashed with brine and dried with Na₂SO₄. After filtration, the filtratewas concentrated and purified by column chromatography on silica gelwith 5 to 25% gradient of ethyl acetate/hexane. The purification wasunsuccessful and gave the product 19a as a crude orange solid (0.158 g,0.333 mmol, 32.3%). Crude product was moved to the next step withoutfurther purification. TLC R_(f) (25% EtOAc/Hexane)=0.53. ¹H NMR(CDCl₃-d, 600 MHz): δ ppm 7.92 (2H, d, J=8.2 Hz), 7.61 (1H, d, J=16 Hz),7.59 (2H, d, J=8.2 Hz), 7.40 (2H, d, J=8.9 Hz), 6.69 (2H, d, J=8.9 Hz),6.23 (1H, d, J=16 Hz), 4.58 (2H, s), 4.23 (2H, q, J=7.14 Hz), 3.49 (2H,q, J=7.08), 2.48 (3H, s), 2.45 (1H, s), 1.30 (3H, t, J=7.14 Hz), 1.22(3H, t, J=7.08 Hz). ¹³C NMR (CDCl₃-d, 150 MHz): δ ppm 167.71, 163.21,152.10, 149.66, 148.89, 144.65, 136.74, 132.07, 131.28 (q, ²J_(FC)=32Hz), 129.95, 129.03, 126.52, 126.32, 125.83 (q, ³J_(FC)=3.8 Hz), 124.84(q, ¹J_(FC)=270 Hz), 123.04, 113.35, 112.40, 60.12, 46.73, 45.24, 15.41,14.38, 12.20.

4-[N-Ethyl-N-[5-methylene-4-methyl-2-[4-(trifluormethyl)phenyl]thiazole]]aminocinnamicAcid (JM-1-15)

To a stirred solution of ethyl ester 19a (0.132 g, 0.278 mmol) in THF (4ml) and 95% ethanol (4 ml) was added 3 N NaOH (1 ml) slowly. Thereaction mixture was stirred at room temperature overnight and uponcompletion was diluted with EtOAc, quenched with acidified water (HCl,pH=3), washed with brine, dried with Na₂SO₄, and filtered. The filtratewas concentrated then purified by column chromatography with a gradientof 15% to 45% ethyl acetate/hexanes with dropwise amounts of acetic acidto give the desired product JM-1-15 as orange solid (0.061 g, 0.137mmol, 49%). TLC R_(f) (50% EtOAc/Hexanes)=0.43. Mp 198° C. ¹H NMR(Acetone-d₆, 600 MHz): δ ppm 8.09 (2H, d, J=8.9 Hz), 7.78 (2H, d, J=8.2Hz), 7.58 (1H, d, J=16 Hz), 7.52 (2H, d, J=8.9 Hz), 6.86 (2H, d, J=8.9Hz), 6.27 (1H, d, J=16 Hz), 4.82 (2H, s), 3.62 (2H, q, J=7 Hz), 2.51(3H, s), 1.25 (3H, t, J=7 Hz). ¹³C NMR (Acetone-d₆, 150 MHz): δ ppm168.45, 162.97, 150.80, 150.05, 145.83, 138.08, 133.86, 131.43 (q,²J_(FC)=32 Hz), 130.80, 127.21, 126.82 (q, ³J_(FC)=4 Hz), 126.03 (q,¹J_(FC)=270 Hz), 123.88, 113.76, 113.36, 47.22, 45.92, 15.49, 12.52.Anal. Calcd for C₂₃H₂₁F₃N₂O₂S with 0.17 mol per target CDCl₃: C, 59.60;H, 4.53; N, 6.00. Found: C, 59.56; H, 4.75; N, 5.96.

Ethyl 4-[N-Isopropyl-N-(tert-butoxycarbonyl)]aminocinnamate (17b)

Ethyl 4-aminocinnamate-BOC 10 (0.840 g, 2.885 mmol) was dissolved in DMF(20 mL) and NaH (60% dispersion in mineral oil, 0.262 g, 6.550 mmol) wasadded while reaction vessel was in an ice bath. The solution was stirredfor 1 hour and 2-iodopropane (1 mL, 10.1 mmol) was added. The reactionwas allowed to warm to room temperature and was stirred overnight.Reaction mixture was quenched with saturated NaHCO₃ and extracted withether three times. The ether extracts were combined and washed withbrine, dried with Na₂SO₄, and filtered. The crude material was purifiedby column chromatography with a gradient of 5% to 10% EtOAc/hexane togive the desired product 17b as a yellow oil (0.488 g, 1.46 mmol, 50%).TLC R_(f) (25% EtOAc/Hexane)=0.58. H NMR (CDCl₃, 600 MHz): δ ppm 7.69(1H, d, J=15.9 Hz), 7.50 (2H, d, J=8.3 Hz), 7.11 (2H, d, J=8.3 Hz), 6.42(1H, d, J=16.0 Hz), 4.50 (1H, sep, J=6.8 Hz), 4.27 (2H, q, J=7.14 Hz),1.38 (9H, s), 1.35 (3H, t, J=7.14 Hz), 1.13 (6H, d, J=6.8 Hz). C NMR(CDCl₃, 150 MHz): δ ppm 166.97, 154.56, 143.86, 141.33, 132.97, 130.26,128.21, 118.40, 80.02, 60.56, 48.80, 28.35, 21.55, 14.34.

Ethyl 4-(N-Isopropyl)aminocinnamate (18b)

Ethyl ester 17b (1.05 g, 3.149 mmol) was dissolved with anhydrous DCM(25 mL). The solution was placed in an ice bath and cooled to 0° C.before TFA (8 mL) was added. After 1.5 hours, the reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography to give the desired product 18b as a white solid (0.609g, 2.613 mmol, 83.0%). TLC R_(f)=0.11 (25% EtOAc/Hexane). Mp 112-115° C.¹H NMR (CDCl₃, 600 MHz): δ ppm 7.59 (1H, d, J=15.84 Hz), 7.35 (2H, d,J=8.52 Hz), 6.54 (2H, d, J=8.64 Hz), 6.20 (1H, d, J=15.84 Hz), 4.23 (2H,q, J=7.14 Hz), 3.67 (1H, sept., J=6.3 Hz), 1.32 (3H, t, J=7.14 Hz), 1.22(6H, d, J=6.3 Hz) (2H, m). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.91,149.19, 145.11, 130.00, 123.15, 112.82, 112.61, 60.08, 44.12, 22.84,14.43. Anal. Calcd for C₁₄H₁₉NO₂: C, 72.07; H, 8.21; N, 6.00. Found: C,72.03; H, 8.30; N, 5.98.

Ethyl4-[N-Isopropyl-N-[5-methylene-4-methyl-2-(4-trifluoromethylphenyl)thiazole]]aminocinnamate(19b)

N-isopropyl ester 18b (0.490 g, 2.100 mmol), thiazole 4b (0.745 g, 2.554mmol) and NaI (0.41 g, 2.735 mmol) were dissolved in dry DMF (25 mL) andcooled to 0° C. NaH (0.107 g, 2.675 mmol) was added and the reactionmixture was stirred for 4 hours at room temperature. The mixture wasdiluted with a solution of NaHCO₃ and extracted with ether three times.The ether extracts were combined and washed with brine, water, driedwith Na₂SO₄, and filtered. Attempts to purify crude sample by columnchromatography failed and the crude product 19b was moved to next stepwithout further purification (0.181 g, 0.370 mmol, 18%). TLC R_(f) (25%EtOAc/Hexane)=0.35. Mp 80-82° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.93(2H, d, J=8.19 Hz), 7.61 (2H, d, J=8.19 Hz), 7.57 (1H, s), 7.39 (H, d,J=15.84 Hz), 4.23 (2H, q, J=8.14 Hz), 3.67 (1H, sep, J=6.3 Hz), 1.32(3H, t, J=7.14 Hz), 1.22 (6H, d, J=6.3 Hz) (2H, m). ¹³C NMR (CDCl₃, 150MHz): δ ppm 167.74, 163.15, 149.79, 148.21, 144.57, 136.80, 134.71,131.15 (q, ²J_(FC)=32 Hz), 129.79, 127.45, 126.26, 125.81 (q,³J_(FC)=3.5 Hz), 124.35 (q, ¹J_(FC)=270 Hz), 113.69, 60.19, 49.02,41.53, 20.00, 15.59, 14.39. Anal. Calcd for C₂₆H₂₇N₂O₂S with 0.4 per moltarget H₂O: C, 62.99; H, 5.65; N, 5.65. Found: C, 62.75; H, 5.49; N,5.58.

4-[N-Isopropyl-N-[5-methylene-4-methyl-2-(4-trifluoromethylphenyl)thiazole]]aminocinnamicAcid (JF-1-13

N-isopropyl ester 19b (0.168 g, 0.344 mmol) was dissolved in EtOH (5 mL)and THF (5 mL) and cooled in ice bath. 3N NaOH (1 mL) was added and thereaction mixture was stirred at room temperature overnight. Reactionmixture was concentrated and the resulting residue was suspended inEtOAc and washed with acidified water (HCl, pH=3), water, brine, driedwith Na₂SO₄, and filtered. The filtrate was purified by columnchromatography with a gradient of 5% to 30% EtOAc/hexane to give thedesired product JF-1-13 as a white solid (0.122 g, 0.266 mmol, 77.1%).TLC R_(f) (50% EtOAc/Hexane)=0.52. Mp 208-210° C. ¹H NMR (CDCl₃, 600MHz): δ ppm 8.20 (2H, d, J=8.1 Hz), 7.88 (2H, d, J=8.3 Hz), 7.67 (1H, d,J=15.9 Hz), 7.62 (2H, d, J=8.9 Hz), 7.0 (2H, d, J=9.0 Hz), 6.36 (1H, d,J=15.8 Hz), 4.53 (1H, sept., J=6.6 Hz), 2.63 (3H, s), 2.07 (2H, s), 1.43(6H, d, J=6.6 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.34, 161.79,150.14, 148.66, 144.78, 137.34, 135.51, 130.31 (q, ²J_(FC)=32 Hz),129.72, 126.21, 125.91 (q, ³J_(FC)=3.5 Hz), 124.27 (q, ¹J_(FC)=270 Hz),123.58, 113.68, 49.04, 41.09, 19.57, 19.15, 14.71. Anal. Calcd forC₂₄H₂₃F₃N₂O₂S: C, 62.60; H, 5.03; N, 6.08. Found: C, 62.30; H, 5.09; N,6.03.

Ethyl 4-[N-Propyl-N-(tert-butoxycarbonyl)]aminocinnamate (17c)

To a stirred solution of Ethyl 4-aminocinnamate-BOC 10 (2.147 g, 7.374mmol) in anhydrous DMF (25 mL) under inert gas at 0° C. was added NaH(60% dispersion in mineral oil, 0.314 g, 7.850 mmol). Mixture stirredfor 1 hour and 1-Iodopropane (2.2 mL, 22.558 mmol) was then added andmixture continued to stir at room temperature overnight. The reactionmixture was then diluted with 50% sodium bicarbonate solution andextracted with ether 3 times. The ether extracts were combined andwashed with brine, dried with Na₂SO₄, filtered and concentrated. Theresidue was concentrated then purified by column chromatography onsilica gel with a gradient of 100% Hexanes to 10% ethyl acetate/hexanesto give the desired product 17c as a yellow solid (2.290 g, 6.868 mmol,93.2%). TLC R_(f) (25% EtOAc/Hexane)=0.59. Mp 56° C. ¹H NMR (CDCl₃, 600MHz): δ ppm 7.66 (1H, d, J=16 Hz), 7.48 (2H, d, J=8.4 Hz), 7.22 (2H, d,J=8.4 Hz), 6.39 (1H, d, J=16 Hz), 4.27 (2H, q, J=7.14 Hz), 3.61 (2H, q,J=7.4 Hz), 1.57 (2H, q, J=7.4 Hz), 1.43 (9H, s), 1.34 (3H, t, J=7.14Hz), 0.88 (3H, t, J=7.4 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.12,154.50, 144.52, 143.94, 131.80, 128.50, 127.03, 118.02, 80.54, 60.60,51.53, 28.41, 21.91, 14.44, 11.56. Anal. Calcd for C₁₉H₂₇NO₄: C, 68.44;H, 8.16; N, 4.20. Found: C, 68.46; H, 8.22; N, 4.22.

Ethyl 4-(N-Propyl)aminocinnamate (18c)

To a stirred solution of ethyl ester 17c (2.080 g, 6.238 mmol) inanhydrous DCM (30 mL) under inert gas at 0° C. was added trifluoroaceticacid (8 mL) slowly. The mixture was allowed to warm to room temperatureand stirred for 2 hours. The mixture was then concentrated and residuewas taken up in EtOAc and washed with cold saturated NaHCO₃, brine, anddried with sodium sulfate. After filtration, the filtrate wasconcentrated and purified by column chromatography on silica gel with agradient of 10% to 20% EtOAc/hexane to give an orange solid 18c (0.573g, 2.455 mmol, 39.4%). TLC R_(f) (25% EtOAc/Hexane)=0.43. Mp 78° C. ¹HNMR (CDCl₃, 600 MHz): δ ppm 7.61 (1H, d, J=16 Hz), 7.38 (2H, d, J=8 Hz),6.61 (2H, d, J=8 Hz), 6.23 (1H, d, J=16 Hz), 4.25 (2H, q, J=7.14 Hz),3.13 (2H, t, J=7.3 Hz), 1.68 (2H, q, J=7.3 Hz), 1.33 (3H, t, J=7.14 Hz),1.00 (3H, t, J=7.3 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.97, 149.60,145.11, 130.06, 129.23, 124.16, 133.22, 60.28, 46.01, 22.50, 14.54,11.67. Anal. Calcd for C₁₃H₁₇F₄NO₂ (with 0.13 mol CDCl₃ per targetcontaminant): C, 68.17; H, 7.69; N, 5.63. Found: C, 68.09; H, 7.50; N,5.53.

Ethyl4-[N-Propyl-N-[5-methylene-4-methyl-2-[4-(trifluormethyl)phenyl]aminocinnamate(19c)

To a stirred solution of ethyl ester 18c (0.237 g, 1.014 mmol), thiazole4b (0.325 g, 1.115 mmol), and NaI (0.231 g, 1.542 mmol) in anhydrous DMF(15 mL) and was added NaH (0.045, 1.896 mmol) slowly while at 0° C. Themixture then stirred at rt for 4 hours. Then the mixture was quenchedwith 50% NaHCO₃ and extracted with ether three times. The ether extractswere combined and washed with brine and dried with Na₂SO₄. The residuewas concentrated then purified by column chromatography on silica gelwith 10 to 30% gradient of EtOAc/hexane to give the desired product 19cas an orange solid (0.294 g, 0.603 mmol, 60%). TLC R_(f) (25%EtOAc/Hexane)=0.35. Mp 128-129° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.97(2H, d, J=8.2 Hz), 7.64 (2H, d, J=8.2 Hz), 7.61 (1H, d, J=16 Hz), 7.43(2H, d, J=8.9 Hz), 6.75 (2H, m), 6.25 (1H, d, J=16 Hz), 4.66 (2H, s),4.25 (2H, q, J=7.14 Hz), 3.40 (2H, t, J=7.4 Hz), 2.50 (3H, s), 1.72 (2H,q, J=7.6 Hz), 1.33 (3H, t, J=7.14 Hz), 0.99 (3H, t, J=7.4 Hz). ¹³C NMR(CDCl₃, 150 MHz): δ ppm 167.89, 163.61, 149.79, 148.99, 144.73, 136.68,131.92, 131.60 (²J_(FC)=32 Hz), 130.05, 126.58, 126.01 (³J_(FC)=3.9 Hz),124.92 (¹J_(FC)=270 Hz), 123.69, 113.65, 112.69, 60.32, 53.18, 47.66,20.62, 15.57, 14.53, 11.56. Anal. Calcd for C₂₆H₂₇F₃N₂O₂S: C, 63.92; H,5.57; N, 5.73. Found: C, 63.71; H, 5.55; N, 5.65.

4-[N-Propyl-N-[5-methylene-4-methyl-2-[4-(trifluormethyl)phenyl]]aminocinnamicAcid (JM-1-12)

To a stirred solution of ethyl ester 19c (0.165 g, 0.337 mmol) in THF (5mL) and 95% ethanol (5 ml) was added 3 N NaOH (1 ml) slowly. The mixturewas stirred at room temperature overnight and taken up in EtOAc thenquenched with acidified water (HCl, pH=3), washed with brine and driedwith Na₂SO₄. The residue was concentrated then purified by columnchromatography on silica gel with a gradient of 15% to 50% EtOAc/hexanesupplemented with drop-wise amounts of acetic acid to give the desiredcompound JM-1-12 as orange solid (0.134 g, 0.290 mmol, 86.1%). TLC R_(f)(50% EtOAc/Hexanes)=0.36. Mp 205° C. ¹H NMR (Acetone-d6, 600 MHz): δ ppm8.10 (2H, d, J=8.2 Hz), 7.78 (2H, d, J=8.2 Hz), 7.58 (1H, d, J=16 Hz),7.52 (2H, d, J=8.9 Hz), 6.85 (2H, d, J=8.9 Hz), 6.26 (1H, d, J=16 Hz),4.85 (2H, s), 3.51 (2H, q, J=7.5 Hz), 2.51 (3H, s), 1.74 (2H, sex, J=7.5Hz), 0.99 (3H, J=7.5 Hz). ¹³C NMR (Acetone-d₆, 150 MHz): δ ppm 168.35,162.94, 150.85, 150.24, 145.83, 138.09, 133.72, 131.43 (²J_(FC)=32 Hz),130.76, 127.21, 126.83 (³J_(FC)=4 Hz), 126.04 (¹J_(FC)=270 Hz), 123.82,113.70, 113.37, 53.49, 47.80, 21.17, 15.50, 11.49. Anal. Calcd forC₂₄H₂₃F₃N₂O₂S: C, 62.60; H, 5.03; N, 6.08. Found: C, 62.20; H, 5.04; N,6.03.

4-Bromo-2-methylbenzaldehyde (21a)

4-Bromo-2-methylbenzonitrile 20a (1.859 g, 9.483 mmol) was dissolved inanhydrous toluene (40 mL) under nitrogen and was cooled to −78° C.Reagent grade DIBAL-H (1.70 mL, 9.538 mmol) was added slowly and mixturewas stirred for 30 minutes. Anhydrous methanol (3 mL) was carefullyadded followed by 2M H₂SO₄ (9 mL) dropwise. Mixture was stirredovernight at r.t. The mixture was diluted with ethyl acetate (50 mL) andthe organic phase was collected, dried with Na₂SO₄, and concentrated.The crude material was purified with flash chromatography using 5%EtOAc/hexane to give 20a as an off-white solid (1.590 g, 7.988 mmol,84.2%). TLC R_(f) (25% EtOAc/Hexane)=0.80. Mp 29-30° C. ¹H NMR (CDCl₃,600 MHz): δ ppm 10.22 (1H, s), 7.66 (1H, d, J=8.22), 7.51 (1H, dd,J₁=8.22, J₂=1.92), 7.45 (1H, s), 2.65 (3H, s). ¹³C NMR (CDCl₃, 150 MHz):δ ppm 191.76, 142.86, 134.86, 133.35, 133.02, 129.83, 129.01, 19.40.

tert-Butyl-N-methylcarbamate

Di-tert-butyl dicarbonate (10.91 g, 49.98 mmol) was dissolved inanhydrous THF (30 mL) under nitrogen and was cooled in ice bath. 2 MMethylamine in THF (50.0 mL, 0.1 mol) was added slowly and mixture wasallowed to warm to r.t and was stirred overnight. Solvent was removedusing rotary evaporation and the resulting residue was taken up into 1 MHCl and DCM. The organic phase was collected and the aqueous phase wasextracted with a separate portion of DCM. The organic phases werecombined and washed with water, dried with sodium sulfate, andconcentrated. Residual solvents were removed using Kugelrohrdistillation to give the title compound as light yellow oil (6.476 g,49.37 mmol, 98.7%). ¹H NMR (CDCl₃, 600 MHz): δ ppm 4.43 (1H, bs), 2.73(3H, d, J=4.92 Hz), 1.45 (9H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm156.74, 79.25, 28.57, 27.26. Anal. Calcd for C₆H₁₃NO₂ (with 0.1 mol H₂Oand 0.1 mol DCM per target): C, 51.79; H, 9.55; N, 9.90. Found: C,51.70; H, 9.34; N, 9.73.

2-Methyl-4-[N-(tert-butoxycarbonyl)methyl]benzaldehyde (22a)

Aldehyde 21a (1.286 g, 6.461 mmol), tert-Butyl-N-methylcarbamate (1.015g, 7.737 mmol), and Cs₂CO₃ (2.958 g, 9.078 mmol) were dissolved inanhydrous dioxane (40 mL) and under nitrogen. Xantphos (0.175 g, 0.302mmol) and Pd₂(dba)₃ (0.136 g, 0.148 mmol) were measured out in nitrogenbag and added to the reaction flask. The reaction mixture was refluxedwith stirring overnight and was then cooled to room temperature beforeremoval of the solvent under reduced pressure. The resulting residue wastaken up into EtOAc and water followed by filtration through celite. TheEtOAc phase was collected and washed with water, brine, and dried withNa₂SO₄. After filtration, the filtrate was concentrated and the residuewas purified using column chromatography and a 100% hexane to 5%EtOAc/hexane mobile phase gradient to give the desired product 22a as ayellow oil (0.976 g, 3.914 mmol, 60.6%). TLC R_(f) (25%EtOAc/hexane)=0.53. ¹H NMR (CDCl₃, 600 MHz): δ ppm 10.21 (1H, s), 7.77(1H, d, J=8.4 Hz), 7.29 (1H, d, J=2.2 Hz), 7.20 (1H, d, J=1.7 Hz), 3.31(3H, s), 2.67 (3H, s), 1.50 (9H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm191.65, 154.21, 148.54, 141.42, 132.72, 130.94, 127.38, 122.27, 81.40,36.91, 28.46, 19.75. Anal. Calcd for C₁₄H₁₉NO₃ (with 0.1H₂O and 0.1 molDCM per target): C, 65.24; H, 7.53; N, 5.40. Found: C, 65.27; H, 7.18;N, 5.06.

Methyl 2-Methyl-4-[N-(tert-butoxycarbonyl)methyl]aminocinnamate (23a)

Aldehyde 22a (0.591 g, 2.371 mmol) andmethyl(triphenylphosphoranylidene)acetate (0.876 g, 2.620 mmol) weredissolved in anhydrous THF (10 mL) under nitrogen gas and stirred at 55°C. for 2 days. The reaction mixture was concentrated and the resultingcrude solid was taken up into EtOAc and washed with water, brine, anddried with Na₂SO₄. After filtration, the filtrate was concentrated andpurified using column chromatography with a 5% to 15% EtOAc/hexanegradient to give the desired product 23a as a yellow oil (0.548 g, 1.794mmol, 75.7%). TLC R_(f) (25% EtOAc/hexane)=0.53. ¹H NMR (CDCl₃, 600MHz): δ ppm 7.94 (1H, d, J=15.9 Hz), 7.51 (1H, d, J=9.1 Hz), 7.11 (2H,m), 6.34 (1H, d, J=15.9 Hz), 3.81 (3H, s), 3.26 (3H, s), 2.42 (3H, s),1.47 (9H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.70, 154.56, 145.35,141.94, 138.31, 130.16, 127.00, 126.78, 123.11, 118.33, 80.87, 60.54,51.83, 37.14, 28.46, 20.06. Anal. Calcd for C₁₇H₂₃NO₄ (with 0.1 mol H₂Oper target): C, 66.47; H, 7.61; N, 4.56. Found: C, 66.26; H, 7.44; N,4.56.

Methyl 2-Methyl-4-(N-methyl)aminocinnamate (24a)

Methyl 2-Methyl-4-[N-(tert-butoxycarbonyl)methyl]aminocinnamate 23a(0.516 g, 1.689 mmol) was taken up into anhydrous DCM (10 mL) undernitrogen gas and cooled in an ice bath. Trifluoroacetic acid (4 mL) wasadded slowly and the mixture was stirred at room temperature for 1.5hours. The reaction mixture was concentrated and the residue was takenup into EtOAc and washed with chilled sat. NaHCO₃, brine, and dried withNa₂SO₄. After filtration, the filtrate was concentrated and the filtratewas purified using column chromatography and a 10% to 20% EtOAc/hexanemobile phase gradient to give the product 24a as a yellow solid (0.229g, 1.116 mmol, 66.1%). TLC (25% EtOAc/hexane)=0.31. Mp 79-83° C. ¹H NMR(CDCl₃, 600 MHz): δ ppm 7.93 (1H, d, J=15.7 Hz), 7.47 (1H, d, J=8.5 Hz),6.45 (1H, dd, J₁=8.5 Hz, J₂=2.5 Hz), 6.20 (1H, d, J=15.8 Hz), 4.11 (1H,bs), 3.78 (3H, s), 2.86 (3H, s), 2.39 (3H, s). ¹³C NMR (CDCl₃, 150 MHz):δ ppm 168.51, 150.94, 142.66, 139.97, 128.13, 122.18, 113.62, 113.10,110.61, 51.52, 30.41, 20.26. Anal. Calcd for C₁₂H₁₅NO₂: C, 70.22; H,7.37; N, 6.82. Found: C, 70.00; H, 7.26; N, 6.68.

Methyl2-Methyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]-thiazole]]aminocinnamate(25a)

Methyl ester 24a (0.316 g, 1.540 mmol), thiazole 4b (0.520 g, 1.782mmol), and NaI (0.328 g, 2.188 mmol) were dried in vacuum desiccatorovernight to ensure dry starting reagents. These starting reagents werecombined in a two-neck flask under nitrogen and anhydrous DMF (15 mL)was added. The reaction mixture was cooled in ice bath and NaH (60%dispersion in mineral oil, 0.101 g, 2.525 mmol) was added by brieflyexposing the system to air. The mixture was warmed to room temperatureand stirred for 2.5 hours. The reaction mixture was quenched with watercarefully and diluted with ether and neutralized with NaHCO₃. Additionalwater was added to obtain a clear two phase solution. The organic phasewas collected and the aqueous phase was extracted with two portions ofether. The organic phases were combined and washed with water, brine,dried with Na₂SO₄. After filtration, the filtrate was concentrated andthe residue was purified by column chromatography with a 5% to 20%EtOAc/hexane mobile phase gradient to give the product 25a as ayellow-orange solid (0.523 g, 1.136 mmol, 73.8%). TLC (25%EtOAc/hexane)=0.33. Mp 151-152° C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.96(2H, d, J=8.2 Hz), 7.93 (1H, d, J=15.8 Hz), 7.64 (2H, d, J=8.2 Hz), 7.53(1H, d, J=8.8 Hz), 6.66 (1H, dd, J₁=8.8 Hz, J₂=2.7 Hz), 6.58 (1H, d,J=2.5 Hz), 6.24 (1H, d, 8.8 Hz), 4.67 (2H, s), 3.79 (3H, s), 3.04 (3H,s), 2.51 (3H, s), 2.43 (3H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 168.35,163.65, 150.31, 149.90, 142.29, 139.88, 136.73, 131.51 (q, ²J_(FC)=32.4Hz), 131.02, 128.18, 126.57, 126.02 (q, ³J_(FC)=3.5 Hz), 124.03 (q,¹J_(FC)=271 Hz), 122.88, 114.52, 114.21, 111.08, 51.64, 49.06, 38.33,20.65, 15.56. Anal. Calcd for C₂₄H₂₃N₂F₃O₂S: C, 62.60; H, 5.03; N, 6.08.Found: C, 62.36; H, 5.06; N, 6.05.

2-Methyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamicAcid (BK-5-15)

Methyl ester 25a (0.400 g, 0.868 mmol) was dissolved in anhydrous THF(10 mL) and 95% ethanol (5 mL) and was cooled in an ice bath. Upon,cooling a precipitate formed but then returned to solution after theaddition of 3N NaOH (1 mL). The reaction mixture was stirred overnightat room temperature and was then concentrated under reduced pressure.The resulting residue was taken up into EtOAc and washed with acidicwater (pH=3, HCl), brine, and dried with Na₂SO₄. After filtration, thefiltrate was concentrated and the residue was purified by columnchromatography using a 25% EtOAc/hexane mobile phase that wassupplemented with dropwise amounts of acetic acid. The column purifiedproduct was collected and recrystallized using 95% ethanol to giveBK-5-15 as a yellow solid (0.081 g, 0.181 mmol, 20.9%). TLC (50%EtOAc/hexane)=0.46. Mp 228-230° C. ¹H NMR (Acetone-d₆, 600 MHz): δ ppm8.10 (2H, d, J=8.1 Hz), 7.90 (1H, d, J=15.8 Hz), 7.79 (2H, d, J=8.3 Hz),7.64 (1H, d, J=8.7 Hz), 6.78 (1H, dd, J₁=9.0 Hz, J₂=2.8 Hz), 6.75 (1H,d, J=2.6 Hz), 6.25 (1H, d, J=15.8 Hz), 4.86 (2H, s), 3.10 (3H, s), 2.52(3H, s), 2.41 (3H, s). ¹³C NMR (Acetone-d₆, 150 MHz): δ ppm 167.44,162.18, 150.51, 150.19, 141.91, 139.23, 137.18, 131.77, 130.51 (q,²J_(FC)=31.8 Hz), 127.93, 126.38, 125.95 (m), 124.25 (q, ¹J_(FC)=271Hz), 122.00, 114.21, 113.79, 111.00, 48.08, 37.50, 19.42, 14.60. Anal.Calcd for C₂₃H₂₁F₃N₂O₂S: C, 61.87; H, 4.74; N, 6.27. Found: C, 61.15; H,4.86; N, 6.18.

4-Bromo-3-methylbenzaldehyde (21b)

4-Bromo-3-methylbenzonitrile (2.100 g, 10.71 mmol) was dissolved inanhydrous toluene (40 mL) under nitrogen and cooled in dry ice bath to−78° C. DIBAL-H was then added and the reaction mixture was stirred at−78° C. for 45 minutes. Anhydrous methanol (3 mL) followed by 2M H₂SO₄(10 mL) were carefully added to the reaction mixture and was stirredovernight at room temperature. The reaction mixture was diluted withEtOAc, washed with water, and dried with Na₂SO₄. After filtration, thefiltrate was concentrated and purified by column chromatography using a100% hexane to 5% EtOAc/hexane mobile phase gradient. The desiredproduct 21b was collected as a white solid (1.801 g, 9.051 mmol, 84.5%).TLC (25% EtOAc/hexane)=0.70. Mp 120-122° C. ¹H NMR (CDCl₃, 600 MHz): δppm 9.95 (1H, s), 7.72 (1H, s), 7.70 (1H, d, J=8.1 Hz), 7.55 (1H, d,J=8.0 Hz), 2.48 (3H, d). ¹³C NMR (CDCl₃, 600 MHz): δ ppm 191.55, 139.27,135.53, 133.36, 132.36, 131.58, 128.40, 23.03. Anal. Calcd. for C₈H₇OBr:C, 48.27; H, 3.54; N, 0.00. Found: C, 48.01; H, 3.56; N, 0.13.

3-Methyl-4-[N-(tert-butoxycarbonyl)methyl]benzaldehyde (22b)

Aldehyde 21b (1.423 g, 7.149 mmol), tert-Butyl-N-methylcarbamate (1.123g, 8.561 mmol), and Cs₂CO₃ (3.323 g, 10.15 mmol) were dissolved inanhydrous dioxane (40 mL) and under nitrogen. Xantphos (0.195 g, 0.337mmol) and Pd₂(dba)₃ (0.149 g, 0.163 mmol) were measured out in nitrogenbag and added to the reaction flask. The reaction mixture was refluxedwith stirring overnight and was then cooled to room temperature beforeremoval of the solvent under reduced pressure. The resulting residue wastaken up into EtOAc and water followed by filtration through celite. TheEtOAc phase was collected and washed with water, brine, and dried withNa₂SO₄. After filtration, the filtrate was concentrated and the residuewas purified using column chromatography and a 100% hexane to 5%EtOAc/hexane mobile phase gradient to give the desired product 22b as alight-yellow, almost colorless oil (0.837 g, 3.357 mmol, 47.0%). TLC(25% EtOAc/hexane)=0.41. ¹H NMR (CDCl₃, 600 MHz): δ ppm 9.98 (1H, s),7.75 (1H, s), 7.71 (1H, d, J=7.7 Hz), 3.17 (3H, s), 2.30 (3H, s), 1.53(3H, s), 1.34 (7H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 191.84, 154.49,148.27, 136.80, 135.07, 132.16, 128.46, 128.18, 80.54, 36.69, 28.36,17.79. Anal. Calcd for C₁₄H₁₉O₃N: C, 67.45; H, 7.68; N, 5.62. Found: C,67.26; H, 7.73; N, 5.67.

Methyl 3-Methyl-4-[N-(tert-butoxycarbonyl)methyl]aminocinnamate (23b)

Aldehyde 22b (0.736 g, 2.953 mmol) andmethyl(triphenylphosphoranylidene)acetate (1.087 g, 3.251 mmol) weredissolved in anhydrous THF (10 mL) and was refluxed for 2 days. Thereaction mixture was concentrated with reduced pressure and the residuewas taken up into EtOAc and washed in water, brine, and dried withNa₂SO₄. After filtration, the filtrate was concentrated and the residuewas purified using column chromatography and a 100% hexane to 7%EtOAc/hexane mobile phase gradient to give the desired product 23b as alight yellow oil (0.561 g, 1.837 mmol, 62.2%). TLC (25%EtOAc/hexane)=0.43. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.66 (1H, d, J=16Hz), 7.37 (1H, s), 7.35 (1H, d, J=7.9 Hz), 7.09 (1H, d, J=7.9 Hz), 6.42(1H, d, J=15.8 Hz), 3.80 (3H, s), 3.14 (3H, s), 2.23 (3H, s), 1.51 (3H,s), 1.33 (7H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.57, 154.86,144.47, 144.37, 136.17, 133.16, 130.57, 127.91, 126.50, 117.91, 80.17,51.87, 36.79, 28.38, 17.75. Anal. Calcd for C₁₇H₂₃O₄N: C, 66.86; H,7.59; N, 4.59. Found: C, 66.57; H, 7.57; N, 4.55.

Methyl 3-Methyl-4-(N-methyl)aminocinnamate (24b)

Methyl ester 23b (1.359 g, 4.450 mmol) was dissolved in anhydrous DCM(25 mL) under nitrogen gas and cooled in ice bath. Trifluoroacetic acid(7 mL, 91.48 mmol) was carefully added and the reaction mixture wasstirred for 2 hours at room temperature. The reaction mixture was thenquenched with an aqueous saturated solution of NaHCO₃. The organic phasewas collected and washed with water, brine, and dried with Na₂SO₄. Afterfiltration, the solution was concentrated and column chromatography wasattempted to purify the crude material along with recrystallization.Purification methods were unsuccessful and the crude yellow solid 24b(0.758 g, 3.693 mmol, 83.0%) was moved to the next step. TLC (25%EtOAc/hexane)=0.36. ¹H NMR (CDCl₃, 400 MHz): δ ppm 7.63 (1H, d, J=16.0Hz), 7.35 (1H, dd, J₁=8.4 Hz, J₂=2.0 Hz), 6.57 (1H, d, J=8.4 Hz), 6.24(1H, d, J=15.6 Hz), 3.77 (3H, s), 2.93 (3H, s), 2.13 (3H, s).

Methyl2-Methyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]-thiazole]]aminocinnamate(25b)

Methyl ester 24b (0.200 g, 0.974 mmol), thiazole 4b (0.340 g, 1.166mmol), and NaI (0.215 g, 1.434 mmol) were dried in vacuum desiccatorovernight to ensure dry starting reagents. These starting reagents werecombined in a two-neck flask under nitrogen and anhydrous acetonitrile(25 mL) was added. The reaction mixture was cooled in ice bath andN,N-Diisopropylethylamine (0.255 g, 1.464 mmol) was added. The mixturewas warmed to room temperature and stirred overnight. TLC showed anincomplete reaction and the mixture was heated to 80° C. for 6 hours.The reaction mixture was concentrated under reduced pressure and thesolid residue was taken up into DCM and water. The organic phase wascollected and the aqueous phase was extracted with a separate portion ofDCM. The two organic phases were combined and dried with Na₂SO₄. Afterfiltration, the filtrate was concentrated and the residue was purifiedby column chromatography with a 5% to 13% EtOAc/hexane mobile phasegradient to give the product 25b as a yellow solid (0.341 g, 0.740 mmol,76.0%). TLC (25% EtOAc/hexane)=0.50. Mp 92-94° C. ¹H NMR (CDCl₃, 600MHz): δ ppm 8.00 (2H, d, J=8.1 Hz), 7.65 (3H, m), 7.39 (1H, d, J=1.6Hz), 7.35 (1H, dd, J₁=8.2 Hz, J₂=2.0 Hz), 7.04 (1H, d, J=8.2 Hz), 6.37(1H, d, J=16.0 Hz), 4.23 (2H, s), 3.80 (3H, s), 2.72 (3H, s), 2.43 (6H,s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.86, 164.05, 153.14, 151.00,144.71, 136.94, 133.26, 131.56, 131.31, 131.13 (m), 129.73, 126.92,126.57, 126.02 (q, ³J_(FC)=3.5 Hz), 124.98, 124.08 (q, ²J_(FC)=270 Hz),120.39, 116.31, 51.98, 51.79, 41.06, 18.78, 15.50. Anal. Calcd forC₂₄H₂₃F₃N₂O₂S: C, 62.60; H, 5.03; N, 6.08. Found: C, 62.08; H, 5.06; N,5.93.

2-Methyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamicAcid (BK-5-99)

Methyl ester 25b (0.220 g, 0.478 mmol) was dissolved in 95% ethanol (6mL) and THF (6 mL). 3N NaOH (2 mL) was added and the mixture was stirredfor 3 days at room temperature. 3N HCl was added until the mixturereached a pH of 3. The mixture was concentrated under reduced pressureand the residue was taken up into EtOAc. The solution was washed withchilled a saturated NaHCO₃ aqueous solution, brine, and dried withNa₂SO₄. After filtration, the filtrate was concentrated and the crudeproduct purified using column chromatography and a 25% EtOAc/hexanemobile phase that was supplemented with dropwise amounts of acetic acid.The column product was recrystallized using 95% ethanol to give BK-5-99as a pale yellow solid (0.170 g, 0.382 mmol, 79.8%). ¹H NMR (Acetone-d₆,600 MHz): δ ppm 10.66 (1H, bs), 8.14 (2H, d, J=8.1 Hz), 7.81 (2H, d,J=8.2 Hz), 7.62 (1H, d, J=16.0 Hz), 7.55 (1H, s), 7.48 (1H, dd, J₁=8.2Hz, J₂=1.7 Hz), 7.19 (1H, d, J=8.3 Hz), 6.44 (1H, d, J=16.0 Hz), 4.37(2H, s), 2.75 (3H, s), 2.45 (3H, s), 2.42 (3H, s). ¹³C NMR (Acetone-d₆,150 MHz): δ ppm 168.01, 163.73, 154.14, 151.99, 145.41, 138.29, 134.14,132.76, 131.93, 131.45 (q, ²J_(FC)=31.9 Hz), 130.58, 127.81, 127.35,126.92 (q, ³J_(FC)=3.8 Hz), 125.24 (q, ¹J_(FC)=270 Hz), 121.48, 117.46,52.15, 41.54, 18.75, 15.54. ¹⁹F NMR (Acetone-d6, 376 MHz): δ ppm −63.62(3F, s). Anal. Calcd for C₂₃H₂₁F₃N₂O₂S: C, 61.87; H, 4.74; N, 6.27.Found: C, 61.69; H, 4.58; N, 6.14.

3-Ethyl-N-(tert-butoxycarbonyl)aniline (27a)

3-Ethylaniline (3.0 mL, 0.024 mol) and di-tert-butyldicarbonate (5.840g, 0.026 mol) were dissolved in anhydrous THF (40 mL) under inert gas.The mixture was refluxed at 65° C. overnight. The reaction mixture wasthen concentrated under reduced pressure and the resulting residue wastaken up into EtOAc and washed with saturated NaHCO₃ solution, water,brine, and dried with Na₂SO₄. After filtration and evaporation of thesolvent, the crude product was purified with column chromatography using10% EtOAc/hexane. The purified product 27a was collected as an orangeoil containing EtOAc (5.837 g, 0.026 mol, 110%). TLC R_(f) (25%EtOAc/Hexane)=0.64. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.20 (1H, m), 7.12(1H, d, J=7.7 Hz), 6.88 (1H, d, J=7.5 Hz), 6.43 (1H, bs), 2.62 (2H, q,J=7.6 Hz), 1.52 (9H, s), 1.22 (3H, t, J=7.6 Hz). ¹³C NMR (CDCl₃, 150MHz): δ ppm 152.91, 145.47, 138.42, 129.00, 122.77, 118.15, 115.97,80.52, 29.06, 28.50, 15.70. Anal. Calcd for C₁₃H₁₉NO₂: C, 70.56; H,8.65; N, 6.33. Found: C, 70.27; H, 8.52; N, 6.10.

3-Ethyl-[N-(tert-butoxycarbonyl)methyl]aniline (28a)

3-Ethyl-(N-tert-butoxycarbonyl)aniline 27a (4.547 g, 20.55 mmol) wasdissolved in anhydrous DMF (50 mL) and cooled in an ice bath. NaH (60%dispersion in mineral oil, 1.234 g, 30.85 mmol) was added and themixture was stirred for 45 minutes followed by addition of iodomethane(3.8 mL, 61.04 mmol). The reaction mixture was stirred overnight at roomtemperature and quenched with 50% saturated NaHCO₃ and extracted withtwo portions of ether. The ether extracts were combined and washed withbrine, dried with Na₂SO₄, and concentrated. The crude material waspurified by column chromatography using 5% EtOAc/hexane to give thedesired product 28a as a yellow-orange oil (4.318 g, 18.35 mmol, 89.3%).TLC R_(f) (25% EtOAc/Hexane)=0.62. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.24(1H, m), 7.07 (1H, s), 7.03 (1H, d, J=7.9 Hz), 7.00 (1H, d, J=7.6 Hz),3.25 (3H, s), 2.66 (2H, q, J=7.6 Hz), 1.45 (9H, s), 1.23 (3H, t, J=7.6Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 155.00, 144.84, 143.94, 128.53,125.26, 125.07, 122.80, 80.26, 37.53, 28.90, 28.50, 15.65. Anal. Calcdfor C₁₄H₂₁NO₂: C, 71.46; H, 9.00; N, 5.95. Found: C, 71.17; H, 8.89; N,5.85.

3-Ethyl-(N-methyl)aniline (29a)

3-Ethyl-[N-(tert-butoxycarbonyl)methyl]aniline 27a (3.582 g, 15.22 mmol)was dissolved in anhydrous DCM (40 mL) under inert gas and cooled in anice bath. Trifluoroacetic acid (10 mL, 0.13 mol) was slowly added andthe mixture was stirred at r.t. for 1.5 hours. The reaction mixture wasdiluted with DCM and neutralized with chilled saturated NaHCO₃. Theorganic phase was collected and washed with water, brine, dried withNa₂SO₄, and concentrated. The crude material was purified by columnchromatography using a gradient of 5% EtOAc/hexane to 50% EtOAc/hexaneand appeared to oxidize upon collection to give the desired product 29aas a crude black oil with trace EtOAc (2.845 g). This material was usedin the next step without further purification. TLC R_(f) (25%EtOAc/Hexane)=0.61. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.36 (1H, m), 7.28(2H, m), 7.24 (1H, d, J=7.6 Hz), 2.99 (3H, s), 2.66 (2H, q, J=7.6 Hz),1.22 (3H, t, J=7.6 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 147.25, 137.64,130.31, 129.07, 121.51, 119.34, 38.08, 28.73, 15.24.

3-Ethyl-[N-methyl-N-[(5-methylene-4-methyl-2-(4-(trifluoromethyl)phenyl)]thiazole]aniline(30a)

3-Ethyl-(N-methyl)aniline 29a (0.693 g, 5.125 mmol), thiazole 4b (1.478g, 5.069 mmol), and NaI (0.790 g, 5.271 mmol) were dissolved inanhydrous DMF (20 mL) under inert gas and cooled in an ice bath. NaH(60% dispersion in mineral oil, 0.314 g, 7.85 mmol) was carefully addedto the reaction by briefly exposing the system to air. The reactionmixture was stirred for 3 hours at room temperature and quenched with a50% dilution of sat. NaHCO₃. The mixture was extracted with threeportions of ether which were combined, washed with brine, dried withNa₂SO₄, and concentrated. The crude material was purified by columnchromatography using a gradient of 5% EtOAc/hexane to 30% EtOAc/hexaneto give the desired product 30a as an orange oil (0.650 g, 1.66 mmol,32.8%). TLC R_(f) (25% EtOAc/Hexane)=0.56. ¹H NMR (CDCl₃, 600 MHz): δppm 7.96 (2H, d, J=8.1 Hz), 7.63 (2H, d, J=8.3 Hz), 7.19 (1H, m), 6.68(3H, m), 4.61 (2H, s), 2.97 (3H, s), 2.62 (2H, q, J=7.6 Hz), 2.50 (3H,s), 1.24 (3H, t, J=7.6 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 163.34,150.07, 149.04, 145.54, 136.87, 131.18 (q, ²J_(FC)=32.5 Hz), 129.27,126.37, 125.82 (m), 123.96 (q, ¹J_(FC)=270 Hz), 118.00, 113.45, 111.24,49.89, 38.41, 29.32, 15.69, 15.44. Anal. Calcd. for C₂₁H₂₁F₃N₂S: C,64.60; H, 5.42; N, 7.17. Found: C, 64.31; H, 5.48; N, 7.01.

2-Ethyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminobenzaldehyde (31a)

Anhydrous DMF (1.0 mL, 12.92 mmol) was added to reaction flask andcooled in an ice bath. POCl₃ (0.5 mL, 5.364 mmol) was slowly added andthe mixture was stirred for 15 minutes. Aniline product 30a (0.612 g,1.567 mmol) from the previous reaction was dissolved with anhydrous DMF(1 mL) in a separate flask. The aniline product solution was carefullytransferred to the reaction flask containing the Vilsmeier reagent. Thereaction mixture was stirred for 2.5 hours at 70° C. and then allowed tocool before being poured onto crushed ice. This mixture was neutralizedwith 3N NaOH until a pH of 10 was reached. This mixture produced noprecipitate and was extracted with two portions of ether. The etherextracts were combined, washed with brine, dried with Na₂SO₄, andconcentrated. The crude material was purified by column chromatographyusing a gradient of 5% EtOAc/hexane to 20% EtOAc/hexane to give thedesired product 31a as a yellow-orange solid (0.432 g, 1.032 mmol,65.9%). TLC R_(f) (25% EtOAc/Hexane)=0.28. Mp 97-98° C. ¹H NMR (CDCl₃,600 MHz): δ ppm 10.02 (1H, s), 7.95 (2H, d, J=8.2 Hz), 7.73 (1H, d,J=8.7 Hz), 7.63 (2H, d, J=8.3 Hz), 6.69 (1H, dd, J₁=8.7 Hz J₂=2.6 Hz),6.57 (1H, d, J=2.5 Hz), 4.74 (2H, s), 3.12 (3H, s), 3.02 (2H, q, J=7.5Hz), 2.53 (3H, s), 1.26 (3H, t, J=7.5 Hz). ¹³C NMR (CDCl₃, 150 MHz): δppm 190.26, 163.76, 152.40, 150.51, 149.64, 136.59, 134.89, 131.60 (q,²J_(FC)=32.5 Hz), 130.33, 126.58, 126.02 (m), 123.99 (q, ¹J_(FC)=271Hz), 123.95, 112.80, 109.78, 48.65, 38.30, 26.68, 16.42, 15.56. Anal.Calcd. for C₂₂H₂₁F₃N₂OS: C, 63.14; H, 5.06; N, 6.69. Found: C, 62.85; H,5.19; N, 6.58.

Ethyl2-Ethyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamate (32a)

Triethylphosphonoacetate (0.24 mL, 1.21 mmol) was taken up intoanhydrous THF (5 mL) in an ice bath and under inert gas. NaH (60%dispersion in mineral oil, 0.055 g, 1.38 mmol) was added by brieflyexposing the system to air. In a separate flask, aldehyde 31a (0.385 g,0.920 mmol) was dissolved in anhydrous THF (5 mL) under inert gas. Afterthe triethylphosphonoacetate mixture had stirred for 30 minutes, thealdehyde solution was added slowly. The reaction mixture was stirred for3 hours at room temperature and upon completion was quenched with sat.NH₄Cl and was extracted with three portions of EtOAc. The combinedorganic layers were washed with brine, dried with Na₂SO₄, andconcentrated. The crude material was purified by column chromatographyusing a gradient of 10% EtOAc/hexane to 20% EtOAc/hexane to give thedesired product 32a as a light yellow solid (0.300 g, 0.614 mmol,66.7%). TLC R_(f) (25% EtOAc/Hexane)=0.38. Mp 127-128° C. ¹H NMR (CDCl₃,600 MHz): δ ppm 7.95 (3H, m), 7.63 (2H, d, J=8.3 Hz), 7.55 (1H, d, J=8.8Hz), 6.65 (1H, dd, J₁=8.8 Hz J₂=2.7 Hz), 6.60 (1H, d, J=2.7 Hz), 6.24(1H, d, J=15.7 Hz), 4.67 (2H, s), 4.25 (2H, q, J=7.1 Hz), 3.04 (3H, s),2.77 (2H, q, J=7.6 Hz), 2.52 (3H, s), 1.33 (3H, t, J=7.1 Hz), 1.23 (3H,t, J=7.6 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 167.96, 163.57, 150.34,150.20, 146.00, 141.78, 136.84, 131.45 (q, J_(FC)=32.6 Hz), 131.15,128.23, 126.53, 125.98 (m), 124.05 (q, ¹J_(FC)=270 Hz), 122.02, 114.81,112.97, 111.11, 60.31, 49.03, 38.26, 27.10, 16.28, 15.59, 14.55. Anal.Calcd. for C₂₆H₂₇F₃N₂O₂S: C, 63.92; H, 5.57; N, 5.73. Found: C, 63.66;H, 5.61; N, 5.58.

2-Ethyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamicAcid (BK-5-67)

Ethyl ester 32a (0.279 g, 0.571 mmol) was dissolved in 95% ethanol (8mL) and THF (8 mL). 3N NaOH (2 mL) was added and the mixture was stirredovernight at room temperature. The reaction was determined incompleteand additional 3N NaOH (2 mL) was added. The mixture was stirred for anadditional 24 hours and was neutralized with 1N HCl to a pH of 3. Thesolvent was removed under reduced pressure and the residue was taken upinto EtOAc, washed with sat. NaHCO₃, brine, dried with Na₂SO₄, andconcentrated. The crude material was purified by column chromatographyusing a 25% EtOAc/hexane to 50% EtOAc/hexane gradient supplemented withdropwise amounts of acetic acid to give the desired product BK-5-67 as ayellow solid (0.181 g, 0.393 mmol, 68.8%). TLC R_(f) (50%EtOAc/Hexane)=0.45. Mp 216-218° C. ¹H NMR (Acetone-d6, 600 MHz): δ ppm8.10 (2H, d, J=8.1 Hz), 7.93 (1H, d, J=15.7 Hz), 7.78 (2H, d, J=8.3 Hz),7.66 (1H, d, J=8.8 Hz), 6.78 (2H, m), 6.26 (1H, d, J=15.7 Hz), 4.86 (2H,s), 3.10 (3H, s), 2.77 (2H, q, J=7.6 Hz), 2.52 (3H, s), 1.20 (3H, t,J=7.6 Hz). ¹³C NMR (Acetone-d6, 150 MHz): δ ppm 168.47, 163.20, 151.53,151.40, 146.50, 142.60, 138.17, 132.74, 131.48 (q, ²J_(FC)=32.1 Hz),129.00, 127.38, 126.95 (m), 125.25 (q, ¹J_(FC)=271 Hz), 122.06, 114.91,113.90, 112.14, 49.10, 38.49, 27.54, 16.73, 15.61. ¹⁹F NMR (Acetone-d6,376 MHz): δ ppm −63.66. Anal. Calcd. for C₂₄H₂₃F₃N₂O₂S: C, 62.60; H,5.03; N, 6.08. Found: C, 62.45; H, 5.07; N, 6.24.

3-Isopropyl-N-(tert-butoxycarbonyl)aniline (27b)

3-Isopropylaniline (1.087 g, 8.039 mmol) and di-tert-butyl dicarbonate(1.988 g, 9.109 mmol) were dissolved in THF (50 mL) under inert gas andheated to reflux at 65° C. for 3 days. The mixture was cooled to roomtemperature and concentrated under reduced pressure. The resultingresidue was taken up into EtOAc and washed with sat. NaHCO₃, water,brine, dried with Na₂SO₄, and concentrated. The crude sample waspurified using column chromatography with a 5% EtOAc/hexane mobile phaseto give the product 27b as a light orange solid (1.660 g, 7.054 mmol,87.7%). TLC R_(f) (25% EtOAc/Hexane)=0.70. Mp 44-45° C. ¹H NMR (CDCl₃,600 MHz): δ ppm 7.25 (1H, br-s), 7.21 (1H, m), 7.15 (1H, d, J=7.4 Hz),6.91 (1H, d, J=7.5 Hz), 6.47 (1H, br-s), 2.87 (1H, sept., J=7.0 Hz),1.52 (9H, s), 1.24 (6H, d, J=7.0 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm152.92, 150.08, 138.40, 128.99, 121.28, 116.86, 116.17, 80.48, 34.31,28.50, 24.07. Anal. Calcd for C₁₄H₂₁NO₂: C, 71.46; H, 9.00; N, 5.95.Found: C, 71.72; H, 9.03; N, 5.86.

3-Isopropyl-[N-methyl-N-(tert-butoxycarbonyl)]aniline (28b)

3-Isopropyl-N-(tert-butoxycarbonyl)aniline 27b (3.148 g, 13.38 mmol) wasdissolved in anhydrous DMF (50 mL) and cooled in an ice bath. NaH (60%dispersion in oil, 0.805 g, 20.13 mmol) was added and the mixture wasstirred for 30 minutes followed by addition of iodomethane (2.5 mL,40.16 mmol). The reaction mixture was stirred overnight at roomtemperature and quenched with a 50% NaHCO₃ solution and extracted twicewith ether. The ether extracts were combined and washed with brine,dried with Na₂SO₄, and concentrated. The crude material was purified bycolumn chromatography using a 100% Hexane to 5% EtOAc/Hexane gradientgiving the desired compound 28b as an orange oil (2.769 g, 11.10 mmol,83.0%). TLC R_(f)(25% EtOAc/Hexane)=0.73. ¹H NMR (CDCl₃, 600 MHz): δ ppm7.24 (1H, t, J=7.8 Hz), 7.09 (1H, bs), 7.03 (2H, dd, J₁=7.7 Hz, J₂=1.6Hz), 3.26 (3H, s), 2.89 (1H, J=6.9 Hz), 1.45 (9H, s), 1.25 (6H, d, J=6.9Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 155.00, 149.45, 143.91, 128.50,124.03, 123.61, 122.77, 80.23, 37.55, 34.19, 28.51, 24.10. Anal. Calcdfor C₁₅H₂₃NO₂: C, 72.25; H, 9.30; N, 5.62. Found: C, 72.53; H, 9.27; N,5.71.

3-Isopropyl-(N-methyl)aniline (29b)

3-Isopropyl-[N-methyl-N-(tert-butoxycarbonyl)]aniline 28b (2.409 g,9.661 mmol) was dissolved in anhydrous DCM (40 mL) under inert gas andcooled in an ice bath. Trifluoroacetic acid (7.4 mL, 96.70 mmol) wasslowly added and the mixture was stirred at r.t. for 2 hours. Thereaction mixture was diluted with DCM and neutralized with chilledsaturated NaHCO₃. The organic phase was collected and washed with water,brine, dried with Na₂SO₄, and concentrated. The crude material waspurified by column chromatography using a gradient of 5% EtOAc/hexane to50% EtOAc/hexane and appeared to oxidize upon collection to give thedesired product 29b as a crude black oil with trace EtOAc (1.733 g).This material was used in the next step without further purification.TLC R_(f) (25% EtOAc/Hexane)=0.51. ¹H NMR (CDCl₃, 600 MHz): δ ppm 7.36(1H, m), 7.26 (1H, m), 2.99 (3H, s), 2.92 (1H, sept., J=6.9 Hz), 1.24(6H, t, J=6.9 Hz). ¹³C NMR (CDCl₃, 150 MHz): δ ppm 151.94, 137.92,130.31, 127.44, 120.05, 119.33, 37.97, 34.15, 23.79.

3-Isopropyl-[N-methyl-N-[(5-methylene-4-methyl-2-(4-(trifluoromethyl)phenyl)]thiazole]aniline(30b)

3-Isopropyl-(N-methyl)aniline 29b (1.352 g, 9.059 mmol), thiazole 4b(1.755 g, 6.016 mmol), and NaI (0.990 g, 6.604 mmol) were dissolved inanhydrous DMF (30 mL) under inert gas and cooled in an ice bath. NaH(60% dispersion in mineral oil, 0.363 g, 9.075 mmol) was carefully addedto the reaction by briefly exposing the system to air. The reactionmixture was stirred for 3 hours at room temperature and quenched with a50% dilution of sat. NaHCO₃. The mixture was extracted with threeportions of ether which were combined, washed with brine, dried withNa₂SO₄, and concentrated. The crude material was purified by columnchromatography using a gradient of 100% hexane to 5% EtOAc/hexane togive the desired product 30b as an orange oil (1.657 g, 4.096 mmol,68.1%). TLC R_(f) (25% EtOAc/Hexane)=0.58. ¹H NMR (CDCl₃, 600 MHz): δppm 7.99 (2H, d, J=8.2 Hz), 7.66 (2H, d, J=8.3 Hz), 7.23 (1H, t, J=8.1Hz), 6.75 (2H, m), 6.70 (1H, m), 4.63 (2H, s), 3.00 (3H, s), 2.88 (1H,sept., J=6.9 Hz), 2.52 (3H, s), 1.27 (6H, d, J=6.9 Hz). ¹³C NMR (CDCl₃,150 MHz): δ ppm 163.55, 162.66, 150.33, 136.97, 133.67, 131.31 (q,²J_(FC)=32.4 Hz), 129.40, 127.58, 126.51, 125.97 (m), 124.08 (q,¹J_(FC)=271 Hz), 116.74, 112.41, 111.69, 50.17, 38.62, 34.65, 24.18,15.57. Anal. Calcd. for C₂₂H₂₃F₃N₂S: C, 65.33; H, 5.73; N, 6.93. Found:C, 65.06; H, 5.67; N, 6.83.

2-Isopropyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminobenzaldehyde (31b)

Anhydrous DMF (1.0 mL, 12.92 mmol) was added to reaction flask andcooled in an ice bath. POCl₃ (0.95 mL, 10.19 mmol) was slowly added andthe mixture was stirred for 15 minutes. Aniline product 30b (1.156 g,2.858 mmol) from the previous reaction was dissolved with anhydrous DMF(2.4 mL) in a separate flask. The aniline product solution was carefullytransferred to the reaction flask containing the Vilsmeier reagent. Thereaction mixture was stirred for 2.5 hours at 70° C. and was thenallowed to cool to room temperature before being poured into ice-cold 1NNaOH forming an orange precipitate. The precipitate was filtered off butgave a sticky solid that could not be easily collected. The solid wasdissolved in ether and combined with two ether extracts collected fromthe filtrate. The ether extracts were washed with brine, dried withNa₂SO₄, and concentrated. The crude material was purified by columnchromatography using a gradient of 5% EtOAc/hexane to 10% EtOAc/hexaneto give the desired product 31b as a yellow oil with some impurities(0.414 g, 0.957 mmol, 33.5%). TLC R_(f) (25% EtOAc/Hexane)=0.28. ¹H NMR(CDCl₃, 600 MHz): δ ppm 10.08 (1H, s), 7.96 (2H, d, J=8.2 Hz), 7.74 (1H,d, J=8.8 Hz), 7.64 (2H, d, J=8.3 Hz), 6.72 (1H, d, J=2.5 Hz), 6.68 (1H,dd, J₁=8.7 Hz J₂=2.6 Hz), 4.74 (2H, s), 4.01 (1H, sept. J=6.8 Hz), 3.13(3H, s), 2.54 (3H, s), 1.28 (6H, d, J=6.8 Hz). ¹³C NMR (CDCl₃, 150 MHz):δ ppm 190.30, 163.81, 154.01, 152.53, 150.52, 136.59, 135.09, 131.62 (q,²J_(FC)=32.5 Hz), 130.39, 126.60, 126.04 (m), 124.00 (q, ¹J_(FC)=270Hz), 123.49, 109.64, 108.85, 48.74, 38.37, 28.07, 23.91, 15.58. Anal.Calcd. for C₂₃H₂₃F₃N₂OS: C, 63.87; H, 5.36; N, 6.48. Found: C, 61.72; H,5.10; N, 6.22.

Ethyl2-Isopropyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamate (32b)

Triethylphosphonoacetate (0.28 mL, 1.41 mmol) was taken up intoanhydrous THF (5 mL) in an ice bath and under inert gas. NaH (60%dispersion in mineral oil, 0.065 g, 1.63 mmol) was added by brieflyexposing the system to air. In a separate flask, aldehyde 31b (0.470 g,1.086 mmol) was dissolved in anhydrous THF (5 mL) under inert gas. Afterthe triethylphosphonoacetate mixture had stirred for 30 minutes, thealdehyde solution was added slowly. The reaction mixture was stirred for3 hours at room temperature and upon completion was quenched with sat.NH₄Cl and was extracted with three portions of EtOAc. The combinedorganic layers were washed with brine, dried with Na₂SO₄, andconcentrated. The crude material was purified by column chromatographyusing a gradient of 10% EtOAc/hexane to 15% EtOAc/hexane to give thedesired product 32b as a yellow solid (0.371 g, 0.739 mmol, 68.0%). TLCR_(f) (25% EtOAc/Hexane)=0.35. Mp 99-100° C. ¹H NMR (CDCl₃, 600 MHz): δppm 8.05 (1H, d, J=15.7 Hz), 7.95 (2H, d, J=8.2 Hz), 7.63 (2H, d, J=8.3Hz), 7.53 (1H, d, J=8.8 Hz), 6.69 (1H, d, J=2.6 Hz), 6.65 (1H, dd,J₁=8.7 Hz J₂=2.6 Hz), 6.23 (1H, d, J=15.6 Hz), 4.67 (2H, s), 4.25 (2H,q, J=7.1 Hz), 3.38 (1H, sept., J=6.8 Hz), 3.05 (3H, s), 2.52 (3H, s),1.33 (3H, t, J=7.1 Hz), 1.25 (6H, d, J=6.8 Hz). ¹³C NMR (CDCl₃, 150MHz): δ ppm 167.92, 163.62, 150.36, 150.22, 149.93, 141.78, 136.80,131.45 (q, ²J_(FC)=32.7 Hz), 128.31, 126.54, 126.00 (m), 124.04 (q,¹J_(FC)=271 Hz), 121.88, 115.40, 111.03, 109.44, 60.33, 49.18, 38.37,29.22, 23.87, 15.60, 14.55. Anal. Calcd. for C₂₇H₂₉F₃N₂O₂S: C, 64.52; H,5.82; N, 5.57. Found: C, 64.45; H, 5.83; N, 5.63.

2-Isopropyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamic Acid (BK-5-82)

Ethyl ester 32b (0.327 g, 0.651 mmol) was dissolved in 95% ethanol (8mL) and THF (8 mL). 3N NaOH (3 mL) was added and the mixture was stirredovernight at room temperature. The reaction was determined incompleteand additional 3N NaOH (3 mL) was added. The mixture was stirred for anadditional 24 hours and was neutralized with 3N HCl to a pH of 3. Theorganic solvent was removed under reduced pressure and the residue wastaken up into EtOAc, washed with sat. NaHCO₃, brine, dried with Na₂SO₄,and concentrated. The crude material was purified by columnchromatography using a 15% EtOAc/hexane to 50% EtOAc/hexane gradientsupplemented with dropwise amounts of acetic acid to give the desiredproduct BK-5-82 as a yellow solid (0.179 g, 0.377 mmol, 57.9%). TLCR_(f) (50% EtOAc/hexane)=0.46. Mp 218-220° C. ¹H NMR (Acetone-d6, 600MHz): δ ppm 10.49 (1H, bs), 8.10 (2H, d, J=8.2 Hz), 8.04 (1H, d, J=15.8Hz), 7.78 (2H, d, J=8.3 Hz), 7.64 (1H, d, J=8.8 Hz), 6.81 (1H, d, J=2.6Hz), 6.77 (1H, dd, J₁=8.8 Hz, J₂=2.6 Hz), 6.25 (1H, d, J=15.6 Hz), 4.88(2H, s), 3.37 (1H, sept., J=6.8 Hz), 3.12 (3H, s), 2.53 (3H, s), 1.25(6H, d, J=6.8 Hz). ¹³C NMR (Acetone-d6, 150 MHz): δ ppm 168.36, 163.12,151.38, 150.21, 142.45, 138.07, 132.73, 131.39 (q, ²J_(FC)=32.3 Hz),128.97, 127.27, 126.84 (m), 125.14 (q, ¹J_(FC)=270 Hz), 121.73, 115.37,111.89, 110.09, 49.13, 38.51, 23.94, 15.54. ¹⁹F NMR (Acetone-d6, 376MHz): δ ppm −63.66. Anal. Calcd. for C₂₅H₂₅F₃N₂O₂S: C, 63.28; H, 5.31;N, 5.90. Found: C, 63.18; H, 5.33; N, 5.98.

Ethyl 5-Methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carboxylate(33)

2-Ketobutyric acid (3.245 g, 0.032 mol) was dissolved in anhydrous DCM(30 mL) under nitrogen gas. Bromine (1.7 mL, 0.033 mol) was slowly addedand the reaction mixture was stirred at room temperature for 15 minutesfollowed by evaporation of the solvent under reduced pressure. Toluenewas added and immediately removed under reduced pressure.4-(Trifluoromethyl)thiobenzamide (6.224 g, 0.303 mol) was added to theresidue, dissolved in 95% ethanol, and refluxed overnight. The solventwas then removed and the residue was purified by column chromatographyusing a DCM mobile phase to give 33 as a white solid (4.140 g, 13.130mmol, 43.3%). TLC (25% EtOAc/hexane)=0.52. Mp 91° C. ¹H NMR (CDCl₃, 600MHz): δ ppm 8.02 (2H, d, J=8.1 Hz), 7.67 (2H, d, J=8.16 Hz), 4.45 (2H,q, J=7.14 Hz), 2.80 (3H, s), 1.43 (3H, s). ¹³C NMR (CDCl₃, 150 MHz): δppm 162.51, 161.91, 145.57, 142.91, 136.08, 131.93 (q, ²J_(FC)=32.5 Hz),130.61, 126.98, 125.98 (q, ³J_(FC)=4.1 Hz), 123.92 (q, ¹J_(FC)=270 Hz),61.44, 14.48, 13.54. Anal. Calcd. for C₁₄H₁₂F₃NO₂S: C, 53.33; H, 3.84;N, 4.44. Found: C, 53.19; H, 3.93; N, 4.35.

4-Hydroxymethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]thiazole (34)

Ethyl ester 33 (3.284 g, 10.416 mmol) was dissolved in anhydrous THF (30mL) under nitrogen gas. The mixture was cooled in ice bath and a chilled2.0 M solution of LAH in THF (5.2 mL, 10.4 mmol) was added slowly. Thereaction mixture was stirred in ice bath for 15 minutes before removingthe ice bath to allow warming to room temperature. The reaction mixturestirred for 90 minutes and was quenched with water and dried withNa₂SO₄. After filtration, the filtrate was concentrated and the residuewas purified by column chromatography using a 10% EtOAc/hexane to 50%EtOAc/hexane mobile phase gradient to give 34 as a yellow solid (1.663g, 6.086 mmol, 58.5%). TLC (25% EtOAc/hexane)=0.16. Mp 112° C. Anal.Calcd. for C₁₂H₁₀F₃NOS: C, 52.74; H, 3.69; N, 5.13. Found: C, 52.67; H,3.77; N, 5.11.

4-Chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]thiazole (35)

Alcohol 34 (1.606 g, 5.877 mmol) was dissolved in anhydrous DCM (40 mL)under nitrogen gas and triethylamine (1.65 mL, 11.838 mmol) was added atroom temperature. The mixture was cooled in an ice bath andmethanesulfonyl chloride (0.69 mL, 8.915 mmol) was added and thereaction mixture was stirred at 4° C. overnight. The reaction mixturewas diluted with DCM and washed with sat. NaHCO₃ solution, water, brine,and dried with Na₂SO₄. After filtration, the filtrate was concentratedand the residue was purified by column chromatography using a 5%EtOAc/hexane to 10% EtOAc/hexane gradient to give 35 as a white solid(1.063 g, 3.643 mmol, 62.0%). TLC (25% EtOAc/hexane)=0.69. Mp 128-129°C. ¹H NMR (CDCl₃, 600 MHz): δ ppm 8.01 (2H, d, J=8.1 Hz), 7.68 (2H, d,J=8.2 Hz), 4.73 (2H, s), 2.55 (3H, s). ¹³C NMR (CDCl₃, 150 MHz): δ ppm162.90, 149.33, 136.56, 133.99, 131.63 (q, ²J_(FC)=32.6), 126.64, 126.06(q, ³J_(FC)=4 Hz), 124.03 (q, ¹J_(FC)=270 Hz), 38.82, 11.66. Anal.Calcd. for C₁₂H₉F₃NSCl: C, 49.41; H, 3.11; N, 4.80. Found: C, 49.40; H,3.06; N, 4.80.

Ethyl4-[N-Methyl-N-[4-methylene-5-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamate(36)

Ethyl ester 35 (0.419 g, 2.041 mmol), thiazole 4b (0.614 g, 2.105 mmol),and NaI (0.463 g, 3.085 mmol) were all dissolved in DMF (20 mL) andcooled in ice bath. NaH (60% dispersion in oil, 0.112 g, 4.654 mmol) wasadded and the reaction mixture was stirred at room temperature for 2.5hours. The reaction mixture was quenched with 50% NaHCO₃ and extractedwith ether three times. The ether extracts were combined and washed withbrine and dried with Na₂SO₄. After filtration, the filtrate wasconcentrated and the residue was purified by column chromatography usinga 10% EtOAc/hexane to 25% EtOAc/hexane to give 36 as a yellow solid(0.725 g, 1.574 mmol, 77.1%). TLC (25% EtOAc/hexane)=0.41. Mp 157-158°C. Anal. Calcd. for C₂₄H₂₃F₃N₂O₂S: C, 62.60; H, 5.03; N, 6.08. Found: C,62.32; H, 5.16; N, 6.05.

4-[N-Methyl-N-[4-methylene-5-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamicAcid (JM-1-39)

Ethyl ester 36 (0.666 g, 1.446 mmol) was dissolved in 95% ethanol (10mL) and THF (10 mL) and cooled in ice bath. 3N NaOH (3 mL) was slowlyadded and the reaction mixture was stirred for 2 days at roomtemperature. The reaction mixture was neutralized with acidic water(HCl, pH=3) and diluted with EtOAc. The organic phase was collected andwashed with water, brine, and dried with Na₂SO₄. After filtration, thefiltrate was concentrated and the residue was purified by columnchromatography using a 15% EtOAc/hexane to 50% EtOAc gradientsupplemented with dropwise amounts of acetic acid to give the desiredproduct JM-1-39 as orange solid (0.089 g, 0.205 mmol, 14.2%). TLC (50%EtOAc/hexane)=0.47. Mp 232-234° C. ¹H NMR (Acetone-d6, 600 MHz): δ ppm8.09 (2H, d, J=8.1 Hz), 7.79 (2H, d, J=8.1 Hz), 7.57 (1H, d, J=15.8 Hz),7.50 (2H, d, J=8.9 Hz), 6.93 (2H, d, J=8.9 Hz), 6.24 (1H, d, J=15.8 Hz),4.74 (2H, s), 3.20 (3H, s), 2.58 (3H, s). ¹³C NMR (Acetone-d6, 150 MHz):δ ppm 168.37, 162.34, 152.11, 151.78, 146.03, 138.02, 132.16, 131.36 (q,²J_(FC)=33 Hz), 130.05, 127.22, 126.88 (q, ³J_(FC)=3.9 Hz), 125.14 (q,¹J_(FC)=270 Hz), 123.38, 113.31, 50.68, 39.20, 11.37. Anal. Calcd. forC₂₂H₉F₃N₂O₂S (with 0.1 mol H₂O per target): C, 60.60; H, 4.48; N, 6.42.Found: C, 60.56; H, 4.57; N, 6.27.

Ethyl5-Methyl-2-[4-(trifluoromethyl)phenyl]-1,2,3-triazole-4-carboxylate (37)

4-(Trifluoromethyl)aniline (0.217 g, 1.347 mmol) was diluted in EtOAcand precipitated using concentrated HCl. The precipitate was collectedand dissolved in water, then added acetic acid (1 mL) and concentratedHCl (0.5 mL) while in ice bath. NaNO₂ (0.103 g, 1.493 mmol) wasdissolved in water and slowly added to the mixture already in the icebath. NaOAc (0.107 g, 1.304 mmol) was dissolved in 1N Na₂CO₃ (1 mL) andadded to a chilled 0° C. solution of ethyl acetoacetate (0.18 mL, 1.42mmol) in EtOH. The resulting solution was slowly added to the firstmixture containing 4-(trifluoromethyl)aniline and the combined mixturewas stirred for two hours at 0° C. The reaction mixture was diluted withEtOAc and washed with water, brine, dried with Na₂SO₄, and filtered. Thefiltrate was concentrated and the residue was dissolved in 95% ethanol(20 mL). Copper chloride dihydrate (0.523 g, 3.068 mmol) and NH₄OAc(1.054 g, 13.674 mmol) were added and the mixture was stirred at refluxtemperature overnight. The reaction mixture was diluted with 2N HCl andextracted with EtOAc. The organic extract was washed with brine, driedwith Na₂SO₄, and filtered. The filtrate was concentrated and purified bycolumn chromatography using a 5% to 10% EtOAc/hexane gradient to givethe desired product 37 as a yellow solid (0.026 g, 0.088 mmol, 6.5%).

5-Methyl-2-[4-(trifluoromethyl)phenyl]-1,2,3-triazole-4-methanol (38)

The method used for synthesis of 38 is analogous to the previouslydescribed method used in the synthesis of 3a-d with the startingreactant being 37.

4-Chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]-1,2,3-triazole(39)

The method used for synthesis of 39 is analogous to the previouslydescribed method used in the synthesis of 4a-d with the startingreactant being 38.

Ethyl4-[N-Methyl-N-[5-methyl-4-methylene-2-[4-(trifluoromethyl)phenyl]-1,2,3-triazole]]aminocinnamate(40)

The method used for synthesis of 40 is analogous to the previouslydescribed method used in the synthesis of 16a-d with the startingreactants being 39 and 15.

4-[N-Methyl-N-[5-methyl-4-methylene-2-[4-(trifluoromethyl)phenyl]-1,2,3-triazole]]aminocinnamicAcid (41)

The method used for synthesis of 41 is analogous to the previouslydescribed method used in the synthesis of BK-4-15 with the startingreactant being 40.

4-[N-Methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamicAlcohol (42)

The method used for synthesis of 42 is analogous to the previouslydescribed method used in the synthesis of 3a-d with the startingreactant being 16b.

4-[N-Methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamonitrile(43)

The method used for synthesis of 43 is analogous to the methods used inthe reference from Zhu, C et. al. that uses the reagents TEMPO, HTIB,NH₄OAc with the starting reactant being 42.

4-[2-(1H-Tetrazol-5-yl)vinyl]-N-methyl-N-[(4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl]aniline(44)

The method used for synthesis of 44 is analogous to the methods used inthe reference from Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001,66, 7945-7950, with the starting reactant being 43.

4-Bromo-N-(tert-butoxycarbonyl)aniline (45)

The method used for synthesis of 45 is analogous to the previouslydescribed method used in the synthesis of 10 with the starting reactantbeing 4-Bromoaniline.

4-Bromo-[N-(tert-butoxycarbonyl)-N-methyl]aniline (46)

The method used for synthesis of 46 is analogous to the previouslydescribed method used in the synthesis of 14 with the starting reactantbeing 45.

4-Bromo-N-(methyl)aniline (47)

The method used for synthesis of 47 is analogous to the previouslydescribed method used in the synthesis of 15 with the starting reactantbeing 46.

4-Bromo-[N-Methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aniline(48)

The method used for synthesis of 48 is analogous to the previouslydescribed method used in the synthesis of 16b with the startingreactants being 47 and 4b.

2-[4-[N-Methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]amino]phenyl]ethene-1-sulfonicAcid, sodium salt (49)

The method used for synthesis of 49 is analogous to the methods used inthe reference from Prakash, G. K. S.; Jog, P. V.; Krishnan, H. S.; Olah,G. A. J. Am. Chem. Soc. 2011, 133(7), 2140-2143, with the startingmaterial being 48.

1,1,1-Trifluoro-3-buten-2-ol (50)

The method used for synthesis of 50 is analogous to the methods used inthe reference from Gajewski, J. J.; Gee, K. R.; Jurayj, J. Org. Chem.1990, 55, 1813-1822, with trifluoroacetaldehyde as starting material.

1,1,1-Trifluoro-4-[4-[N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]methylamino]phenyl]but-3-en-2-ol(51)

The method used for synthesis of 51 is analogous to the methods used inthe reference from Prakash, G. K. S.; Jog, P. V.; Krishnan, H. S.; Olah,G. A. J. Am. Chem. Soc. 2011, 133(7), 2140-2143, with the startingmaterials being 48 and 50.

4-[N-[5-Methylene-4-methyl-2[(4-(trifluoromethyl)phenyl]thiazole]methylamino]styrylphosphonicAcid (53a)

The method used for synthesis of 53a (and 53b, 53c) is analogous to themethods used in the reference from Saha, U.; Helvig, C. F.; Petkovich,P. M. PCT Int. Appl. 2010, WO2010083613, with 52a (and 52b, 52crespectively) and bis-diethylphosphonate as the starting reagents.

4-(Methylamino)benzonitrile (54)

The method used for the synthesis of 54 is analogous to the methods usedin the previously described multistep synthesis of 15 with4-Aminobenzonitrile.

4-[N-[5-Methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]methylamino]benzonitrile(55)

The method used for synthesis of 55 is analogous to the method used inthe previously described synthesis of 16 with 54 and 4b as startingmaterials.

4-[N-[5-Methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]methylamino]styrylboronicAcid (56)

The method used for the synthesis of 56 is analogous to the method usedin the reference from Gopula, Balraj et al. Org Lett. 2014, 16(2),632-635, with 55 as the starting reagent.

Alkyl2-[4-[N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]methylamino]phenyl]ethene-1-sulfonamide (57)

The method used for the synthesis of various analogs of 57 is analogousto the method used in the reference from Rad, M. N. S. et al. Synthesis.2009, 23, 3983-3988, with 49 and primary or secondary amines as thestarting materials.

6-(N-tert-Butoxycarbonyl)amino-2-naphthalenesulfonic Acid (58)

The method used for the synthesis of 58 is analogous to the method usedin the previously described synthesis of 10 with commercially available6-Amino-2-naphthalenesulfonic acid as starting material.

6-[N-(tert-Butoxycarbonyl)methylamino]-2-naphthalenesulfonic Acid (59)

The method used for the synthesis of 59 is analogous to the method usedin the previously described synthesis of 14 with 58 being the startingmaterial.

6-(N-Methylamino)-2-naphthalenesulfonic Acid (60)

The method used for the synthesis of 60 is analogous to the method usedin the previously described synthesis of 15 with 59 being the startingmaterial.

6-[N-[5-Methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]methylamino]-2-naphthalenesulfonicAcid (61)

The method used for the synthesis of 61 is analogous to the method usedin the previously described synthesis of 16 with 60 and 4b being thestarting materials.

Alkyl6-[N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]methylamino]-2-naphthalenesulfonamide(62)

The method used for the synthesis of various analogs of 61 is analogousto the method used in the reference from Rad, M. N. S. et al. Synthesis.2009, 23, 3983-3988, with 62 and primary or secondary amines as thestarting materials.

Certain embodiments of the compounds, compositions, and methodsdisclosed herein are defined in the above examples. It should beunderstood that these examples, while indicating particular embodimentsof the invention, are given by way of illustration only. From the abovediscussion and these examples, one skilled in the art can ascertain theessential characteristics of this disclosure, and without departing fromthe spirit and scope thereof, can make various changes and modificationsto adapt the compositions and methods described herein to various usagesand conditions. Various changes may be made and equivalents may besubstituted for elements thereof without departing from the essentialscope of the disclosure. In addition, many modifications may be made toadapt a particular situation or material to the teachings of thedisclosure without departing from the essential scope thereof.

What is claimed is:
 1. A method of inducing osteogenesis, comprising:administering an effective amount of a pharmaceutical composition to amammalian patient in need thereof, the pharmaceutical compositioncomprising a peroxisome proliferator activated receptor (PPAR) compoundin an amount sufficient to prompt stem cells in the patient tocontribute toward bone formation, and a pharmaceutically acceptablecarrier, excipient, diluent or adjuvant; wherein the PPAR compound has achemical structure of Formula I:

wherein: X is O, S, NH, or N-alkyl; R₁ is H or alkyl; R₂ is H or alkyl;R₃ is H or CF₃; Ra is H, CF₃ or halide; and R₅ is H or alkyl; whereinFormula I cannot be BK-4-15, wherein X is NCH₃; R₁ is H; R₂ is H; R₃ isCF₃; R₄ is H; and R₅ is H, and the method comprised inducingosteogenesis; and, wherein Formula I cannot be JF-4-80, wherein X═S,R₁═R₂═R₅═H, R₃═CF₃ and R₄═F, and the method comprised inducingosteogenesis; and, and salts, isomers, solvates, hydrates, polymorphs,and prodrugs thereof.
 2. The method of claim 1, wherein the compoundcomprises BK-4-03, wherein X═NH, R₁═R₂═R₄═R₅═H and R₃═CF₃.
 3. The methodof claim 1, wherein the compound comprises BK-4-04, wherein X═S,R₁═R₂═R₄═R₅═H and R₃═CF₃.
 4. The method of claim 1, wherein the compoundcomprises BK-5-15, wherein X═NCH₃, R₁═CH₃, R₂═R₄═R₅═H and R₃═CF₃.
 5. Themethod of claim 1, wherein the compound comprises JM-4-57, wherein X═O,R₁═R₂═R₅═H, R₃═CF₃ and R₄═F.
 6. The method of claim 1, wherein themammalian patient is a human.
 7. The method of claim 1, wherein theadministration is by surgical implantation including allograft bone,bone substitutes or bone scaffold matrices, or by localized injection ofliquid or gel formulations or delivery systems to or near the bone. 8.The method of claim 1, wherein the administration is by an intravenous,intramuscular or subcutaneous injection of liquid or gel formulations ordelivery systems.
 9. The method of claim 1, wherein the administrationis by delivery of oral formulations that can additionally containcommonly used excipients for such delivery systems.
 10. A method ofinducing osteogenesis, the method comprising: administering induced stemcells to a mammalian patient in need thereof; wherein the induced stemcells are derived from incubating stem cells with a pharmaceuticalcomposition comprising a peroxisome proliferator activated receptor(PPAR) compound according to claim 1, and having a chemical structure ofFormula I.
 11. The method of claim 10, wherein the mammalian patient isa human and the stem cells are either harvested from the same patient orsupplied from another mammalian donor.
 12. A compound comprising astructure of Formula I:

wherein: X is O, S, NH, NCH₃ NCH₂CH₃, NCH₂CH₂CH₃ or NCH(CH₃)₂; R₁ is H,CH₃, CH₂CH₃ or CH(CH₃)₂; R₂ is H or CH₃; R₃ is H or CF₃; Ra is H, F orCF₃; and R₅ is H,CH₃ or CH₂CH₃; wherein Formula I cannot be X=O, R₁=CH₃,R₂=H, R₃=CF₃, R₄=H, and R₅=CH₃; wherein Formula I cannot be X=O, R₁=CH₃, R₂=H, R₃=CF₃, R₄=H, and R₅=H; wherein Formula I cannot be X=O,R₁=R₂=R₃=H, R₄=CF₃, and R₅=H; wherein Formula I cannot be X=O,R₁=R₂=R₃=H, R₄=CF₃, and R₅=CH₃; wherein Formula I cannot be X=0, R₁=CH₃,R₂=R₃=H, R₄=CF₃, and R₅=CH₃; wherein Formula I cannot be BK-4-03,wherein X=NH, R₁=R₂=R₄=R₅=H and R₃=CF₃; Formula I cannot be BK-4-15,wherein X=NCH₃, R₁=R₂=R₄=R₅=H, R₃=CF₃; and, except wherein Formula Icannot be BK-5-15, wherein X=NCH₃, R₁=CH₃, R₂=R₄=R₅=H, R₃=CF₃; andsalts, isomers, stereoisomers, enantiomers, racemates, solvates,hydrates, polymorphs, and prodrugs thereof.
 13. The compound of claim12, wherein the compound comprises BK-4-04, wherein X=S, R₁=R₂=R₄=R₅=Hand R₃=CF₃.
 14. The compound of claim 12, wherein the compound comprisesJF-4-80, wherein X=S, R₁=R₂=R₅=H, R₃=CF₃ and R₄=F.
 15. The compound ofclaim 12, wherein the compound comprises JM-4-57, wherein X=O,R₁=R₂=R₅=H, R₃=CF₃ and R₄=F.
 16. A compound, comprising a structure offormula II:

wherein: X is O, S, NH, or N-Alkyl; R₁ is H or alkyl; R₂ is H or alkyl;R₃ is H or CF₃; R₄ is H, CF₃ or halide; and Y is

wherein R₅ is H, alkyl or CF₃,

and salts, isomers, solvates, hydrates, polymorphs, and prodrugsthereof.
 17. A compound, comprising a structure of formula IV or V:

wherein: X is O, S, NH, or N-Alkyl; R¹ is H or alkyl; R² is H or alkyl;R³ is H or CF₃; R⁴ is H, CF₃ or halide; and R⁵ is CO₂H, CO₂-alkyl; orone of

wherein R⁶ is H, alkyl or CF₃;

wherein Formula V cannot be X=S, R₁=CH₃ R₂=H, R₃=CF₃ R₄=H, and R₅=CO₂Hor 002-alkyl; and salts, isomers, solvates, hydrates, polymorphs, andprodrugs thereof.
 18. A method of inducing osteogenesis, comprising:administering an effective amount of a pharmaceutical composition to amammalian patient in need thereof either directly to the patient or byharvesting stem cells from the patient or a suitable donor, treating theisolated stem cells and then delivering the treated stem cells to thepatient, the pharmaceutical composition comprising a peroxisomeproliferator activated receptor (PPAR) compound of Formula IV or V

wherein: X is O, S, NH, or N-Alkyl R¹ is H or alkyl R² is H or alkyl R³is H or CF₃ R⁴ is H, CF₃ or halide; and R⁵ is CO₂H, CO₂-alkyl; or one of

wherein R⁶ is H, alkyl or CF₃:

and salts, isomers, solvates, hydrates, polymorphs, and prodrugsthereof, in an amount sufficient to prompt stem cells to contributetoward bone or cartilage formation, and a pharmaceutically acceptablecarrier, excipient, diluent or adjuvant.
 19. The method of claim 1,wherein inducing osteogenesis in the mammalian patient includes therapyfor weakened bones and fractures.
 20. The method of claim 7, wherein thesurgical implantation comprises a joint implant.
 21. The method of claim10, wherein the stem cells are present in a culture media after eitherbeing harvested from a human patient or another mammal; and, whereinafter treatment are administered to a human patient as a therapy forbone fracture, or concurrent with skeletal surgery.